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Sample records for variant hypocrea jecorina

  1. Product inhibition of five Hypocrea jecorina cellulases

    DEFF Research Database (Denmark)

    Murphy, Leigh; Westh, Peter; Bohlin, Christina

    2013-01-01

    Product inhibition of cellulolytic enzymes has been deemed a critical factor in the industrial saccharification of cellulosic biomass. Several investigations have addressed this problem using crude enzyme preparations or commercial (mixed) cellulase products, but quantitative information...... on individual cellulases hydrolyzing insoluble cellulose remains insufficient. Such knowledge is necessary to pinpoint and quantify inhibitory weak-links in cellulose hydrolysis, but has proven challenging to come by. Here we show that product inhibition of mono-component cellulases hydrolyzing unmodified...... cellulose may be monitored by calorimetry. The key advantage of this approach is that it directly measures the rate of hydrolysis while being essentially blind to the background of added product. We investigated the five major cellulases from Hypocrea jecorina (anamorph: Tricoderma reesei), Cel7A (formerly...

  2. Regulation of transcription of cellulases- and hemicellulases-encoding genes in Aspergillus niger and Hypocrea jecorina (Trichoderma reesei)

    NARCIS (Netherlands)

    Stricker, A.R.; Mach, R.L.; Graaff, de L.H.

    2008-01-01

    The filamentous fungi Aspergillus niger and Hypocrea jecorina (Trichoderma reesei) have been the subject of many studies investigating the mechanism of transcriptional regulation of hemicellulase- and cellulase-encoding genes. The transcriptional regulator XlnR that was initially identified in A.

  3. Exo-exo synergy between Cel6A and Cel7A from Hypocrea jecorina

    DEFF Research Database (Denmark)

    Badino, Silke Flindt; Christensen, Stefan Jarl; Kari, Jeppe

    2017-01-01

    Synergy between cellulolytic enzymes is essential in both natural and industrial breakdown of biomass. In addition to synergy between endo- and exo-lytic enzymes, a lesser known but equally conspicuous synergy occurs among exo-acting, processive cellobiohydrolases (CBHs) such as Cel7A and Cel6A...... from Hypocrea jecorina. We studied this system using microcrystalline cellulose as substrate and found a degree of synergy between 1.3 and 2.2 depending on the experimental conditions. Synergy between enzyme variants without the carbohydrate binding module (CBM) and its linker was strongly reduced...... compared to the wild types. One plausible interpretation of this is that exo-exo synergy depends on the targeting role of the CBM. Many earlier works have proposed that exo-exo synergy was caused by an auxiliary endo-lytic activity of Cel6A. However, biochemical data from different assays suggested...

  4. Direct kinetic comparison of the two cellobiohydrolases Cel6A and Cel7A from Hypocrea jecorina

    DEFF Research Database (Denmark)

    Badino, Silke Flindt; Kari, Jeppe; Christensen, Stefan Jarl

    2017-01-01

    Cellulose degrading fungi such as Hypocrea jecorina secrete several cellulases including the two cellobiohydrolases (CBHs) Cel6A and Cel7A. The two CBHs differ in catalytic mechanism, attack different ends, belong to different families, but are both processive multi-domain enzymes that are essent...

  5. Improving the thermal stability of cellobiohydrolase Cel7A from Hypocrea jecorina by directed evolution.

    Science.gov (United States)

    Goedegebuur, Frits; Dankmeyer, Lydia; Gualfetti, Peter; Karkehabadi, Saeid; Hansson, Henrik; Jana, Suvamay; Huynh, Vicky; Kelemen, Bradley R; Kruithof, Paulien; Larenas, Edmund A; Teunissen, Pauline J M; Ståhlberg, Jerry; Payne, Christina M; Mitchinson, Colin; Sandgren, Mats

    2017-10-20

    Secreted mixtures of Hypocrea jecorina cellulases are able to efficiently degrade cellulosic biomass to fermentable sugars at large, commercially relevant scales. H. jecorina Cel7A, cellobiohydrolase I, from glycoside hydrolase family 7, is the workhorse enzyme of the process. However, the thermal stability of Cel7A limits its use to processes where temperatures are no higher than 50 °C. Enhanced thermal stability is desirable to enable the use of higher processing temperatures and to improve the economic feasibility of industrial biomass conversion. Here, we enhanced the thermal stability of Cel7A through directed evolution. Sites with increased thermal stability properties were combined, and a Cel7A variant (FCA398) was obtained, which exhibited a 10.4 °C increase in T m and a 44-fold greater half-life compared with the wild-type enzyme. This Cel7A variant contains 18 mutated sites and is active under application conditions up to at least 75 °C. The X-ray crystal structure of the catalytic domain was determined at 2.1 Å resolution and showed that the effects of the mutations are local and do not introduce major backbone conformational changes. Molecular dynamics simulations revealed that the catalytic domain of wild-type Cel7A and the FCA398 variant exhibit similar behavior at 300 K, whereas at elevated temperature (475 and 525 K), the FCA398 variant fluctuates less and maintains more native contacts over time. Combining the structural and dynamic investigations, rationales were developed for the stabilizing effect at many of the mutated sites. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Crystallization and preliminary X-ray diffraction analysis of the glucuronoyl esterase catalytic domain from Hypocrea jecorina

    International Nuclear Information System (INIS)

    Wood, S. J.; Li, X.-L.; Cotta, M. A.; Biely, P.; Duke, N. E. C.; Schiffer, M.; Pokkuluri, P. R.

    2008-01-01

    The catalytic domain of the glucuronoyl esterase from H. jecorina was overexpresssed, purified and crystallized in space group P2 1 2 1 2 1 . X-ray diffraction data were collected to 1.9 Å resolution. The catalytic domain of the glucuronoyl esterase from Hypocrea jecorina (anamorph Trichoderma reesei) was overexpresssed, purified and crystallized by the sitting-drop vapor-diffusion method using 1.4 M sodium/potassium phosphate pH 6.9. The crystals belonged to space group P2 1 2 1 2 1 and X-ray diffraction data were collected to 1.9 Å resolution. This is the first enzyme with glucoronoyl esterase activity to be crystallized; its structure will be valuable in lignocellulose-degradation research

  7. Crystallization and preliminary X-ray diffraction analysis of the glucuronoyl esterase catalytic domain from Hypocrea jecorina

    Energy Technology Data Exchange (ETDEWEB)

    Wood, S. J. [Biosciences Division, Argonne National Laboratory, Argonne, IL 60439 (United States); Li, X.-L.; Cotta, M. A. [Fermentation Biotechnology Research Unit, National Center for Agricultural Utilization Research, USDA-ARS, Peoria, Illinois 61604 (United States); Biely, P. [Institute of Chemistry, Slovak Academy of Sciences, 845 38 Bratislava (Slovakia); Duke, N. E. C.; Schiffer, M.; Pokkuluri, P. R., E-mail: rajp@anl.gov [Biosciences Division, Argonne National Laboratory, Argonne, IL 60439 (United States)

    2008-04-01

    The catalytic domain of the glucuronoyl esterase from H. jecorina was overexpresssed, purified and crystallized in space group P2{sub 1}2{sub 1}2{sub 1}. X-ray diffraction data were collected to 1.9 Å resolution. The catalytic domain of the glucuronoyl esterase from Hypocrea jecorina (anamorph Trichoderma reesei) was overexpresssed, purified and crystallized by the sitting-drop vapor-diffusion method using 1.4 M sodium/potassium phosphate pH 6.9. The crystals belonged to space group P2{sub 1}2{sub 1}2{sub 1} and X-ray diffraction data were collected to 1.9 Å resolution. This is the first enzyme with glucoronoyl esterase activity to be crystallized; its structure will be valuable in lignocellulose-degradation research.

  8. The role of pheromone receptors for communication and mating in Hypocrea jecorina (Trichoderma reesei)

    Science.gov (United States)

    Seibel, Christian; Tisch, Doris; Kubicek, Christian P.; Schmoll, Monika

    2012-01-01

    Discovery of sexual development in the ascomycete Trichoderma reesei (Hypocrea jecorina) as well as detection of a novel class of peptide pheromone precursors in this fungus indicates promising insights into its physiology and lifestyle. Here we investigated the role of the two pheromone receptors HPR1 and HPR2 in the H. jecorina pheromone-system. We found that these pheromone receptors show an unexpectedly high genetic variability among H. jecorina strains. HPR1 and HPR2 confer female fertility in their cognate mating types (MAT1-1 or MAT1-2, respectively) and mediate induction of fruiting body development. One compatible pheromone precursor–pheromone receptor pair (hpr1–hpp1 or hpr2–ppg1) in mating partners was sufficient for sexual development. Additionally, pheromone receptors were essential for ascospore development, hence indicating their involvement in post-fertilisation events. Neither pheromone precursor genes nor pheromone receptor genes of H. jecorina were transcribed in a strictly mating type dependent manner, but showed enhanced expression levels in the cognate mating type. In the presence of a mating partner under conditions favoring sexual development, transcript levels of pheromone precursors were significantly increased, while those of pheromone receptor genes do not show this trend. In the female sterile T. reesei strain QM6a, transcriptional responses of pheromone precursor and pheromone receptor genes to a mating partner were clearly altered compared to the female fertile wild-type strain CBS999.97. Consequently, a delayed and inappropriate response to the mating partner may be one aspect causing female sterility in QM6a. PMID:22884620

  9. The Hypocrea jecorina (syn. Trichoderma reesei) lxr1 gene encodes a D-mannitol dehydrogenase and is not involved in L-arabinose catabolism

    NARCIS (Netherlands)

    Metz, Benjamin; de Vries, Ronald P; Polak, Stefan; Seidl, Verena; Seiboth, Bernhard

    2009-01-01

    The Hypocrea jecorina LXR1 was described as the first fungal L-xylulose reductase responsible for NADPH dependent reduction of L-xylulose to xylitol in L-arabinose catabolism. Phylogenetic analysis now reveals that LXR1 forms a clade with fungal D-mannitol 2-dehydrogenases. Lxr1 and the orthologous

  10. Differential Involvement of β-Glucosidases from Hypocrea jecorina in Rapid Induction of Cellulase Genes by Cellulose and Cellobiose

    Science.gov (United States)

    Zhou, Qingxin; Xu, Jintao; Kou, Yanbo; Lv, Xinxing; Zhang, Xi; Zhao, Guolei; Zhang, Weixin; Chen, Guanjun

    2012-01-01

    Appropriate perception of cellulose outside the cell by transforming it into an intracellular signal ensures the rapid production of cellulases by cellulolytic Hypocrea jecorina. The major extracellular β-glucosidase BglI (CEL3a) has been shown to contribute to the efficient induction of cellulase genes. Multiple β-glucosidases belonging to glycosyl hydrolase (GH) family 3 and 1, however, exist in H. jecorina. Here we demonstrated that CEL1b, like CEL1a, was an intracellular β-glucosidase displaying in vitro transglycosylation activity. We then found evidence that these two major intracellular β-glucosidases were involved in the rapid induction of cellulase genes by insoluble cellulose. Deletion of cel1a and cel1b significantly compromised the efficient gene expression of the major cellulase gene, cbh1. Simultaneous absence of BglI, CEL1a, and CEL1b caused the induction of the cellulase gene by cellulose to further deteriorate. The induction defect, however, was not observed with cellobiose. The absence of the three β-glucosidases, rather, facilitated the induced synthesis of cellulase on cellobiose. Furthermore, addition of cellobiose restored the productive induction on cellulose in the deletion strains. The results indicate that the three β-glucosidases may not participate in transforming cellobiose beyond hydrolysis to provoke cellulase formation in H. jecorina. They may otherwise contribute to the accumulation of cellobiose from cellulose as inducing signals. PMID:23002106

  11. Evolution and ecophysiology of the industrial producer Hypocrea jecorina (Anamorph Trichoderma reesei and a new sympatric agamospecies related to it.

    Directory of Open Access Journals (Sweden)

    Irina S Druzhinina

    Full Text Available BACKGROUND: Trichoderma reesei, a mitosporic green mould, was recognized during the WW II based on a single isolate from the Solomon Islands and since then used in industry for production of cellulases. It is believed to be an anamorph (asexual stage of the common pantropical ascomycete Hypocrea jecorina. METHODOLOGY/PRINCIPAL FINDINGS: We combined molecular evolutionary analysis and multiple methods of phenotype profiling in order to reveal the genetic relationship of T. reesei to H. jecorina. The resulting data show that the isolates which were previously identified as H. jecorina by means of morphophysiology and ITS1 and 2 (rRNA gene cluster barcode in fact comprise several species: i H. jecorina/T. reesei sensu stricto which contains most of the teleomorphs (sexual stages found on dead wood and the wild-type strain of T. reesei QM 6a; ii T. parareesei nom. prov., which contains all strains isolated as anamorphs from soil; iii and two other hypothetical new species for which only one or two isolates are available. In silico tests for recombination and in vitro mating experiments revealed a history of sexual reproduction for H. jecorina and confirmed clonality for T. parareesei nom. prov. Isolates of both species were consistently found worldwide in pantropical climatic zone. Ecophysiological comparison of H. jecorina and T. parareesei nom. prov. revealed striking differences in carbon source utilization, conidiation intensity, photosensitivity and mycoparasitism, thus suggesting adaptation to different ecological niches with the high opportunistic potential for T. parareesei nom. prov. CONCLUSIONS: Our data prove that T. reesei belongs to a holomorph H. jecorina and displays a history of worldwide gene flow. We also show that its nearest genetic neighbour--T. parareesei nom. prov., is a cryptic phylogenetic agamospecies which inhabits the same biogeographic zone. These two species thus provide a so far rare example of sympatric speciation

  12. Variants of cellobiohydrolases

    Energy Technology Data Exchange (ETDEWEB)

    Bott, Richard R.; Foukaraki, Maria; Hommes, Ronaldus Wilhelmus; Kaper, Thijs; Kelemen, Bradley R.; Kralj, Slavko; Nikolaev, Igor; Sandgren, Mats; Van Lieshout, Johannes Franciscus Thomas; Van Stigt Thans, Sander

    2018-04-10

    Disclosed are a number of homologs and variants of Hypocrea jecorina Ce17A (formerly Trichoderma reesei cellobiohydrolase I or CBH1), nucleic acids encoding the same and methods for producing the same. The homologs and variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted and/or deleted.

  13. Improved cellulolytic efficacy in Penicilium decumbens via heterologous expression of Hypocrea jecorina endoglucanase II

    Directory of Open Access Journals (Sweden)

    Qin Yuqi

    2013-01-01

    Full Text Available Hypocrea jecorina endoglucanase II (Hjegl2 was heterologously expressed in Penicillium decumbens (yielding strain Pd::Hjegl2. After induction in cellulose containing media, strain Pd::Hjeg2 displayed increased carboxymethylcellulase activity (CMCase, 5.77 IU/ml, representing a 21% increase and cellulose degradation determined with a filter paper assay (FPA, 0.40 IU/ml, 67% increase, as compared to the parent strain. In media supplemented with glucose (2%, Pd::Hjegl2, displayed 51.2-fold and 3-fold higher CMCase and FPA activities, respectively, as compared to the parent strain. No changes in the expression levels of the four main native cellulase genes of P. decumbens (Pdegl1, Pdegl2, Pdcbh1, and Pdcbh2 were noted between the transformant and wild-type strains. These data support the idea that Hjegl2 cleaves both internal and terminal glycosidic residues, in a relatively random and processive manner. In situ polyacrylamide gelactivity staining of extracts derived from wild-type and Pd::Hjegl2 revealed two additional active fractions in the latter strain; one with a molecular mass ~50-65 KDa and another ~80-116 kDa.

  14. Impact of light on Hypocrea jecorina and the multiple cellular roles of ENVOY in this process

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    Druzhinina Irina S

    2007-12-01

    Full Text Available Abstract Background In fungi, light is primarily known to influence general morphogenesis and both sexual and asexual sporulation. In order to expand the knowledge on the effect of light in fungi and to determine the role of the light regulatory protein ENVOY in the implementation of this effect, we performed a global screen for genes, which are specifically effected by light in the fungus Hypocrea jecorina (anamorph Trichoderma reesei using Rapid Subtraction Hybridization (RaSH. Based on these data, we analyzed whether these genes are influenced by ENVOY and if overexpression of ENVOY in darkness would be sufficient to execute its function. Results The cellular functions of the detected light responsive genes comprised a variety of roles in transcription, translation, signal transduction, metabolism, and transport. Their response to light with respect to the involvement of ENVOY could be classified as follows: (i ENVOY-mediated upregulation by light; (ii ENVOY-independent upregulation by light; (iii ENVOY-antagonized upregulation by light; ENVOY-dependent repression by light; (iv ENVOY-independent repression by light; and (v both positive and negative regulation by ENVOY of genes not responsive to light in the wild-type. ENVOY was found to be crucial for normal growth in light on various carbon sources and is not able to execute its regulatory function if overexpressed in the darkness. Conclusion The different responses indicate that light impacts fungi like H. jecorina at several cellular processes, and that it has both positive and negative effects. The data also emphasize that ENVOY has an apparently more widespread cellular role in this process than only in modulating the response to light.

  15. Evaluation of a Hypocrea jecorina Enzyme Preparation for Hydrolysis of Tifton 85 Bermudagrass

    Science.gov (United States)

    Ximenes, E. A.; Brandon, S. K.; Doran-Peterson, J.

    Tifton 85 bermudagrass, developed at the ARS-USDA in Tifton, GA, is grown on over ten million acres in the USA for hay and forage. Of the bermudagrass cultivars, Tifton 85 exhibits improved digestibility because the ratio of ether- to ester-linked phenolic acids has been lowered using traditional plant breeding techniques. A previously developed pressurized batch hot water (PBHW) method was used to treat Tifton 85 bermudagrass for enzymatic hydrolysis. Native grass (untreated) and PBHW-pretreated material were compared as substrates for fungal cultivation to produce enzymes. Cellulase activity, measured via the filter paper assay, was higher for fungi cultivated on PBHW-pretreated grass, whereas the other nine enzyme assays produced higher activities for the untreated grass. Ferulic acid and vanillin levels increased significantly for the enzyme preparations produced using PBHW-pretreated grass and the release of these phenolic compounds may have contributed to the observed reduction in enzyme activities. Culture supernatant from Tifton 85 bermudagrass-grown fungi were combined with two commercial enzyme preparations and the enzyme activity profiles are reported. The amount of reducing sugar liberated by the enzyme mixture from Hypocrea jecorina (after 192 h incubation with untreated bermudagrass) individually or in combination with feruloyl esterase was 72.1 and 84.8%, respectively, of the commercial cellulase preparation analyzed under the same conditions.

  16. Light-dependent roles of the G-protein α subunit GNA1 of Hypocrea jecorina (anamorph Trichoderma reesei

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    Kubicek Christian P

    2009-09-01

    Full Text Available Abstract Background The filamentous ascomycete Hypocrea jecorina (anamorph Trichoderma reesei is primarily known for its efficient enzymatic machinery that it utilizes to decompose cellulosic substrates. Nevertheless, the nature and transmission of the signals initiating and modulating this machinery are largely unknown. Heterotrimeric G-protein signaling represents one of the best studied signal transduction pathways in fungi. Results Analysis of the regulatory targets of the G-protein α subunit GNA1 in H. jecorina revealed a carbon source and light-dependent role in signal transduction. Deletion of gna1 led to significantly decreased biomass formation in darkness in submersed culture but had only minor effects on morphology and hyphal apical extension rates on solid medium. Cellulase gene transcription was abolished in Δgna1 on cellulose in light and enhanced in darkness. However, analysis of strains expressing a constitutively activated GNA1 revealed that GNA1 does not transmit the essential inducing signal. Instead, it relates a modulating signal with light-dependent significance, since induction still required the presence of an inducer. We show that regulation of transcription and activity of GNA1 involves a carbon source-dependent feedback cycle. Additionally we found a function of GNA1 in hydrophobin regulation as well as effects on conidiation and tolerance of osmotic and oxidative stress. Conclusion We conclude that GNA1 transmits a signal the physiological relevance of which is dependent on both the carbon source as well as the light status. The widespread consequences of mutations in GNA1 indicate a broad function of this Gα subunit in appropriation of intracellular resources to environmental (especially nutritional conditions.

  17. The crystal structure of the core domain of a cellulose induced protein (Cip1 from Hypocrea jecorina, at 1.5 Å resolution.

    Directory of Open Access Journals (Sweden)

    Frida Jacobson

    Full Text Available In an effort to characterise the whole transcriptome of the fungus Hypocrea jecorina, cDNA clones of this fungus were identified that encode for previously unknown proteins that are likely to function in biomass degradation. One of these newly identified proteins, found to be co-regulated with the major H. jecorina cellulases, is a protein that was denoted Cellulose induced protein 1 (Cip1. This protein consists of a glycoside hydrolase family 1 carbohydrate binding module connected via a linker region to a domain with yet unknown function. After cloning and expression of Cip1 in H. jecorina, the protein was purified and biochemically characterised with the aim of determining a potential enzymatic activity for the novel protein. No hydrolytic activity against any of the tested plant cell wall components was found. The proteolytic core domain of Cip1 was then crystallised, and the three-dimensional structure of this was determined to 1.5 Å resolution utilising sulphur single-wavelength anomalous dispersion phasing (sulphor-SAD. A calcium ion binding site was identified in a sequence conserved region of Cip1 and is also seen in other proteins with the same general fold as Cip1, such as many carbohydrate binding modules. The presence of this ion was found to have a structural role. The Cip1 structure was analysed and a structural homology search was performed to identify structurally related proteins. The two published structures with highest overall structural similarity to Cip1 found were two poly-lyases: CsGL, a glucuronan lyase from H. jecorina and vAL-1, an alginate lyase from the Chlorella virus. This indicates that Cip1 may be a lyase. However, initial trials did not detect significant lyase activity for Cip1. Cip1 is the first structure to be solved of the 23 currently known Cip1 sequential homologs (with a sequence identity cut-off of 25%, including both bacterial and fungal members.

  18. Dehydrogenase GRD1 Represents a Novel Component of the Cellulase Regulon in Trichoderma reesei (Hypocrea jecorina) ▿ † §

    Science.gov (United States)

    Schuster, André; Kubicek, Christian P.; Schmoll, Monika

    2011-01-01

    Trichoderma reesei (Hypocrea jecorina) is nowadays the most important industrial producer of cellulase and hemicellulase enzymes, which are used for pretreatment of cellulosic biomass for biofuel production. In this study, we introduce a novel component, GRD1 (glucose-ribitol dehydrogenase 1), which shows enzymatic activity on cellobiose and positively influences cellulase gene transcription, expression, and extracellular endo-1,4-β-d-glucanase activity. grd1 is differentially transcribed upon growth on cellulose and the induction of cellulase gene expression by sophorose. The transcription of grd1 is coregulated with that of cel7a (cbh1) under inducing conditions. GRD1 is further involved in carbon source utilization on several carbon sources, such as those involved in lactose and d-galactose catabolism, in several cases in a light-dependent manner. We conclude that GRD1 represents a novel enhancer of cellulase gene expression, which by coregulation with the major cellulase may act via optimization of inducing mechanisms. PMID:21602376

  19. Lactosylamidine-based affinity purification for cellulolytic enzymes EG I and CBH I from Hypocrea jecorina and their properties.

    Science.gov (United States)

    Ogata, Makoto; Kameshima, Yumiko; Hattori, Takeshi; Michishita, Kousuke; Suzuki, Tomohiro; Kawagishi, Hirokazu; Totani, Kazuhide; Hiratake, Jun; Usui, Taichi

    2010-12-10

    Selective adsorption and separation of β-glucosidase, endo-acting endo-β-(1→4)-glucanase I (EG I), and exo-acting cellobiohydrolase I (CBH I) were achieved by affinity chromatography with β-lactosylamidine as ligand. A crude cellulase preparation from Hypocrea jecorina served as the source of enzyme. When crude cellulase was applied to the lactosylamidine-based affinity column, β-glucosidase appeared in the unbound fraction. By contrast, EG I and CBH I were retained on the column and then separated from each other by appropriately adjusting the elution conditions. The relative affinities of the enzymes, based on their column elution conditions, were strongly dependent on the ligand. The highly purified EG I and CBH I, obtained by affinity chromatography, were further purified by Mono P and DEAE chromatography, respectively. EG I and CBH I cleave only at the phenolic bond in p-nitrophenyl glycosides with lactose and N-acetyllactosamine (LacNAc). By contrast, both scissile bonds in p-nitrophenyl glycosides with cellobiose were subject to hydrolysis although with important differences in their kinetic parameters. Copyright © 2010 Elsevier Ltd. All rights reserved.

  20. Exo-exo synergy between Cel6A and Cel7A from Hypocrea jecorina: Role of carbohydrate binding module and the endo-lytic character of the enzymes.

    Science.gov (United States)

    Badino, Silke F; Christensen, Stefan J; Kari, Jeppe; Windahl, Michael S; Hvidt, Søren; Borch, Kim; Westh, Peter

    2017-08-01

    Synergy between cellulolytic enzymes is essential in both natural and industrial breakdown of biomass. In addition to synergy between endo- and exo-lytic enzymes, a lesser known but equally conspicuous synergy occurs among exo-acting, processive cellobiohydrolases (CBHs) such as Cel7A and Cel6A from Hypocrea jecorina. We studied this system using microcrystalline cellulose as substrate and found a degree of synergy between 1.3 and 2.2 depending on the experimental conditions. Synergy between enzyme variants without the carbohydrate binding module (CBM) and its linker was strongly reduced compared to the wild types. One plausible interpretation of this is that exo-exo synergy depends on the targeting role of the CBM. Many earlier works have proposed that exo-exo synergy was caused by an auxiliary endo-lytic activity of Cel6A. However, biochemical data from different assays suggested that the endo-lytic activity of both Cel6A and Cel7A were 10 3 -10 4 times lower than the common endoglucanase, Cel7B, from the same organism. Moreover, the endo-lytic activity of Cel7A was 2-3-fold higher than for Cel6A, and we suggest that endo-like activity of Cel6A cannot be the main cause for the observed synergy. Rather, we suggest the exo-exo synergy found here depends on different specificities of the enzymes possibly governed by their CBMs. Biotechnol. Bioeng. 2017;114: 1639-1647. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  1. CBH1 homologs and varian CBH1 cellulase

    Energy Technology Data Exchange (ETDEWEB)

    Goedegebuur, Frits; Gualfetti, Peter; Mitchinson, Colin; Neefe, Paulien

    2014-07-01

    Disclosed are a number of homologs and variants of Hypocrea jecorina Cel7A (formerly Trichoderma reesei cellobiohydrolase I or CBH1), nucleic acids encoding the same and methods for producing the same. The homologs and variant cellulases have the amino acid sequence of a glycosyl hydrolase of family 7A wherein one or more amino acid residues are substituted and/or deleted.

  2. Temperature effects on kinetic parameters and substrate affinity of Cel7A cellobiohydrolases

    DEFF Research Database (Denmark)

    Sørensen, Trine Holst; Cruys-Bagger, Nicolaj; Windahl, Michael Skovbo

    2015-01-01

    Hypocrea jecorina and thermophilic Rasamsonia emersonii and two variants of these enzymes designed to elucidate the role of the carbohydrate binding module (CBM). We consistently found that the maximal rate increased strongly with temperature, whereas the affinity for the insoluble substrate decreased...... for affinity it slows down the catalytic process. Cel7A from the thermophilic organism was moderately more activated by temperature than the mesophilic analog. This is in accord with general theories on enzyme temperature adaptation and possibly relevant information for the selection of technical cellulases....

  3. Purifying Selection and Birth-and-Death Evolution in the Class II Hydrophobin Gene Families of the Ascomycete Trichoderma/Hypocrea

    Energy Technology Data Exchange (ETDEWEB)

    kubicek, Christian P.; Baker, Scott E.; Gamauf, Christian; Kenerley, Chuck; Druzhinina, Irina S.

    2008-01-10

    Hydrophobins are proteins containing eight conserved cysteine residues that occur uniquely in mycelial fungi, where their main function is to confer hydrophobicity to fungal surfaces in contact with air and during attachment of hyphae to hydrophobic surfaces of hosts, symbiotic partners or of themselves resulting in morphogenetic signals. Based on their hydropathy patterns and their solubility characteristics, they are classified in class I and class II hydrophobins, the latter being found only in ascomycetes. Here we have investigated the mechanisms driving the evolution of the class II hydrophobins in nine species of the mycoparasitic ascomycetous genus Trichoderma/Hypocrea, using three fully sequenced genomes (H. jecorina=T. reesei, H. atroviridis=T. atroviride; H. virens=T. virens) and a total of 14.000 ESTs of six others (T. asperellum, H. lixii=T. harzianum, T. aggressivum var. europeae, T. longibrachiatum, T. cf. viride). The former three contained six, ten and nine members, which is the highest number found in any other ascomycete so far. They all showed the conserved four beta-strands/one helix structure, which is stabilized by four disulfide bonds. In addition, a small number of these HFBs contained an extended N-terminus rich in either praline and aspartate, or glycine-asparagine. Phylogenetic analysis reveals a mosaic of terminal clades contain duplicated genes and shows only three reasonably supported clades. Calculation of the ratio of differences in synonymous vs. non-synonymous nucleotide substitutions provides evidence for strong purifying selection (KS/Ka >> 1). A genome database search for class II HFBs from other ascomycetes retrieved a much smaller number of hydrophobins (2-4) from each species, and most of them were from Pyrenomycetes. A combined phylogeny of these sequences with those of Trichoderma showed that the Trichoderma HFBs mostly formed their own clades, whereas those of other pyrenomycetes occured in shared clades. Our study shows

  4. F-16 Microbially Influenced Corrosion (MIC) Characterization & Prevention Study

    Science.gov (United States)

    2011-05-12

    Staphylococcus epidermidis Fungal Consortium Aspergillus fumigatus Fusarium oxysporum Penicillium oxalicum Rhodoturula sp . Trichoderma sp . Control... sp . (FI-18) – Hypocrea jecorina (FI-1) Penicillium oxalicum (FI-12) – Pleosporacea sp . (FI-17) Rhodoturala mucilaginosa (FI-7) – Ustilago maydis (FI...Growth, or Soil and Dirt Accumulation • Fungal Consortium – Aspergillus sp (FI-19) Aureobasidium pullulans (FI-16) – Fusarium oxysporum (FI-6) Fusarium

  5. Microbial Influenced Corrosion (MIC) Study

    Science.gov (United States)

    2012-05-23

    fumigatus Fusarium oxysporum Fungal Consortium Penicillium oxalicum Rhodoturula sp . Trichoderma sp . Dosed with microbes known to influence Control...Hypocrea jecorina (FI-1) Penicillium oxalicum (FI-12) – Pleosporacea sp . (FI-17) Rhodoturala mucilaginosa (FI-7) – Ustilago maydis (FI-13) T t S t• es...and Dirt Accumulation • Fungal Consortium – Aspergillus sp (FI-19) Aureobasidium pullulans (FI-16) – Fusarium oxysporum (FI-6) Fusarium sp . (FI-18

  6. Comparative genome sequence analysis underscores mycoparasitism as the ancestral life style of Trichoderma

    Science.gov (United States)

    2011-01-01

    Background Mycoparasitism, a lifestyle where one fungus is parasitic on another fungus, has special relevance when the prey is a plant pathogen, providing a strategy for biological control of pests for plant protection. Probably, the most studied biocontrol agents are species of the genus Hypocrea/Trichoderma. Results Here we report an analysis of the genome sequences of the two biocontrol species Trichoderma atroviride (teleomorph Hypocrea atroviridis) and Trichoderma virens (formerly Gliocladium virens, teleomorph Hypocrea virens), and a comparison with Trichoderma reesei (teleomorph Hypocrea jecorina). These three Trichoderma species display a remarkable conservation of gene order (78 to 96%), and a lack of active mobile elements probably due to repeat-induced point mutation. Several gene families are expanded in the two mycoparasitic species relative to T. reesei or other ascomycetes, and are overrepresented in non-syntenic genome regions. A phylogenetic analysis shows that T. reesei and T. virens are derived relative to T. atroviride. The mycoparasitism-specific genes thus arose in a common Trichoderma ancestor but were subsequently lost in T. reesei. Conclusions The data offer a better understanding of mycoparasitism, and thus enforce the development of improved biocontrol strains for efficient and environmentally friendly protection of plants. PMID:21501500

  7. Comparative genome sequence analysis underscores mycoparasitism as the ancestral life style of Trichoderma.

    Science.gov (United States)

    Kubicek, Christian P; Herrera-Estrella, Alfredo; Seidl-Seiboth, Verena; Martinez, Diego A; Druzhinina, Irina S; Thon, Michael; Zeilinger, Susanne; Casas-Flores, Sergio; Horwitz, Benjamin A; Mukherjee, Prasun K; Mukherjee, Mala; Kredics, László; Alcaraz, Luis D; Aerts, Andrea; Antal, Zsuzsanna; Atanasova, Lea; Cervantes-Badillo, Mayte G; Challacombe, Jean; Chertkov, Olga; McCluskey, Kevin; Coulpier, Fanny; Deshpande, Nandan; von Döhren, Hans; Ebbole, Daniel J; Esquivel-Naranjo, Edgardo U; Fekete, Erzsébet; Flipphi, Michel; Glaser, Fabian; Gómez-Rodríguez, Elida Y; Gruber, Sabine; Han, Cliff; Henrissat, Bernard; Hermosa, Rosa; Hernández-Oñate, Miguel; Karaffa, Levente; Kosti, Idit; Le Crom, Stéphane; Lindquist, Erika; Lucas, Susan; Lübeck, Mette; Lübeck, Peter S; Margeot, Antoine; Metz, Benjamin; Misra, Monica; Nevalainen, Helena; Omann, Markus; Packer, Nicolle; Perrone, Giancarlo; Uresti-Rivera, Edith E; Salamov, Asaf; Schmoll, Monika; Seiboth, Bernhard; Shapiro, Harris; Sukno, Serenella; Tamayo-Ramos, Juan Antonio; Tisch, Doris; Wiest, Aric; Wilkinson, Heather H; Zhang, Michael; Coutinho, Pedro M; Kenerley, Charles M; Monte, Enrique; Baker, Scott E; Grigoriev, Igor V

    2011-01-01

    Mycoparasitism, a lifestyle where one fungus is parasitic on another fungus, has special relevance when the prey is a plant pathogen, providing a strategy for biological control of pests for plant protection. Probably, the most studied biocontrol agents are species of the genus Hypocrea/Trichoderma. Here we report an analysis of the genome sequences of the two biocontrol species Trichoderma atroviride (teleomorph Hypocrea atroviridis) and Trichoderma virens (formerly Gliocladium virens, teleomorph Hypocrea virens), and a comparison with Trichoderma reesei (teleomorph Hypocrea jecorina). These three Trichoderma species display a remarkable conservation of gene order (78 to 96%), and a lack of active mobile elements probably due to repeat-induced point mutation. Several gene families are expanded in the two mycoparasitic species relative to T. reesei or other ascomycetes, and are overrepresented in non-syntenic genome regions. A phylogenetic analysis shows that T. reesei and T. virens are derived relative to T. atroviride. The mycoparasitism-specific genes thus arose in a common Trichoderma ancestor but were subsequently lost in T. reesei. The data offer a better understanding of mycoparasitism, and thus enforce the development of improved biocontrol strains for efficient and environmentally friendly protection of plants. © 2011 Kubicek et al.; licensee BioMed Central Ltd.

  8. Hexavalent chromium reduction by a hypocrea tawa fungal strain

    International Nuclear Information System (INIS)

    Morales-Battera, L.; Guillen-Jimenez, F. M.; Cristiani-Urbina, E.

    2009-01-01

    Microbial transformation of the highly toxic, water-soluble and mobile hexavalent chromium [Cr(VI)], to the less toxic, insoluble and immobile trivalent chromium [Cr(III)], is an economically feasible alternative for the treatment of wastewaters contaminated with Cr(VI). The main purpose of this work was to isolate, identify and characterize a microbial strain water by batch enrichment culture techniques, and further identified as Hypocrea tawa by its D1/D2 domain sequence of the 26S rRNA gene with 99,44% similarity. (Author)

  9. Development of Specific Substrates for Hypocrea jecorina Cellulases

    DEFF Research Database (Denmark)

    Rasmussen, Tina Secher

      During the last decades a considerable amount of interest has focused on transformation of cellulosic biomass to renewable energy sources such as ethanol.1,2 Cellulases, secreted by different microorganisms, are key enzymes in this process. However, the degradation of cellulose is a difficult......, a commonly encountered problem during this process is the "dying off" of enzymes over time,4 possibly caused by one component in the mixture becoming rate-limiting. Currently, no methodologies exists that can accurately profile, identify and quantify active enzymes in a complex mixture and such a methodology...... of the three-dimensional (X-ray) structures of different cellulases indicated that modifications at other positions would occlude binding, while, typically some space is available around the 4' and 6' position. The substituents were chosen so that further modifications would be possible either by click...

  10. Hypopulvins, novel peptaibiotics from the polyporicolous fungus Hypocrea pulvinata, are produced during infection of its natural hosts

    DEFF Research Database (Denmark)

    Röhrich, Christian René; Iversen, Anita; Jaklitsch, Walter Michael

    2012-01-01

    In order to investigate the significance of antibiotics for the producing organism(s) in the natural habitat, we screened specimens of the polyporicolous fungus Hypocrea pulvinata growing on its natural hosts Piptoporus betulinus and Fomitopsis pinicola. Results showed that a particular group...

  11. Hypocrea rufa/Trichoderma viride: a reassessment, and description of five closely related species with and without warted conidia.

    Science.gov (United States)

    Jaklitsch, Walter M; Samuels, Gary J; Dodd, Sarah L; Lu, Bing-Sheng; Druzhinina, Irina S

    2006-01-01

    The type species of the genus Hypocrea (Hypocreaceae, Hypocreales, Ascomycota, Fungi), H. rufa, is re-defined and epitypified using a combination of phenotype (morphology of teleomorphs and anamorphs, and characteristics in culture) and phylogenetic analyses of the translation-elongation factor 1alpha gene. Its anamorph, T. viride, the type species of Trichoderma, is re-described and epitypified. Eidamia viridescens is combined as Trichoderma viridescens and is recognised as one of the most morphologically and phylogenetically similar relatives of T. viride. Its teleomorph is newly described as Hypocrea viridescens. Contrary to frequent citations of H. rufa and T. viride in the literature, this species is relatively rare. Although both T. viride and T. viridescens have a wide geographic distribution, their greatest genetic diversity appears to be in Europe and North America. Hypocrea vinosa is characterised and its anamorph, T. vinosum sp. nov., is described. Conidia of T. vinosum are subglobose and warted. The new species T. gamsii is proposed. It shares eidamia-like morphology of conidiophores with T. viridescens, but it has smooth, ellipsoidal conidia that have the longest L/W ratio that we have seen in Trichoderma. Trichoderma scalesiae, an endophyte of trunks of Scalesia pedunculata in the Galapagos Islands, is described as new. It only produces conidia on a low-nutrient agar to which filter paper has been added. Additional phylogenetically distinct clades are recognised and provisionally delimited from the species here described. Trichoderma neokoningii, a T. koningii-like species, is described from a collection made in Peru on a fruit of Theobroma cacao infected with Moniliophthora roreri.

  12. A novel platform for heterologous gene expression in Trichoderma reesei (Teleomorph Hypocrea jecorina)

    DEFF Research Database (Denmark)

    Jørgensen, Mikael Skaanning; Skovlund, Dominique Aubert; Johannesen, Pia Francke

    2014-01-01

    ABSTRACT: BACKGROUND: The industrially applied filamentous fungus Trichoderma reesei has received substantial interest due to its highly efficient synthesis apparatus of cellulytic enzymes. However, the production of heterologous enzymes in T. reesei still remains low mainly due to lack of tools...

  13. Surface Plasmon Resonance Imaging of the Enzymatic Degradation of Cellulose Microfibrils

    Science.gov (United States)

    Reiter, Kyle; Raegen, Adam; Clarke, Anthony; Lipkowski, Jacek; Dutcher, John

    2012-02-01

    As the largest component of biomass on Earth, cellulose represents a significant potential energy reservoir. Enzymatic hydrolysis of cellulose into fermentable sugars, an integral step in the production of biofuel, is a challenging problem on an industrial scale. More efficient conversion processes may be developed by an increased understanding of the action of the cellulolytic enzymes involved in cellulose degradation. We have used our recently developed quantitative, angle-scanning surface plasmon resonance imaging (SPRi) device to study the degradation of cellulose microfibrils upon exposure to cellulosic enzymes. In particular, we have studied the action of individual enzymes, and combinations of enzymes, from the Hypocrea Jecorina cellulase system on heterogeneous, industrially-relevant cellulose substrates. This has allowed us to define a characteristic time of action for the enzymes for different degrees of surface coverage of the cellulose microfibrils.

  14. Unraveling the Secondary Metabolism of the Biotechnological Important Filamentous Fungus Trichoderma reesei ( Teleomorph Hypocrea jecorina)

    DEFF Research Database (Denmark)

    Jørgensen, Mikael Skaanning

    that would enable pursuance of the primary objective. The developed molecular tools were assembled into an expression system for high-throughput construction of defined integrated T. reesei mutants and combined inactivation of the non-homologous end joining pathway that facilitates ectopic integration...... of exposed DNA fragments, and a color maker so that the mutants, in which the substrate had been integrated correct, could be identified by their phenotype. A new bidirectional selective marker system was developed based on the pyr2 gene, involved in the pyrimidine biosynthesis pathway, and was included...... essential for biosynthesis of the sorbicillinoids. Hence, genes involved in biosynthesis of this group of polyketides were identified for the first time. Comparative genomics was subsequently used to identify a highly similar polyketide synthase gene cluster in another well-known sorbicillinoid producer...

  15. Xylan oligosaccharides and cellobiohydrolase I (TrCel7A interaction and effect on activity

    Directory of Open Access Journals (Sweden)

    Baumann Martin J

    2011-10-01

    Full Text Available Abstract Background The well-studied cellulase mixture secreted by Trichoderma reesei (anamorph to Hypocrea jecorina contains two cellobiohydolases (CBHs, cellobiohydrolase I (TrCel7A and cellobiohydrolase II (TrCeI6A, that are core enzymes for the solubilisation of cellulose. This has attracted significant research interest because of the role of the CBHs in the conversion of biomass to fermentable sugars. However, the CHBs are notoriously slow and susceptible to inhibition, which presents a challenge for the commercial utilisation of biomass. The xylans and xylan fragments that are also present in the biomass have been suggested repeatedly as one cause of the reduced activity of CHBs. Yet, the extent and mechanisms of this inhibition remain poorly elucidated. Therefore, we studied xylan oligosaccharides (XOSs of variable lengths with respect to their binding and inhibition of both TrCel7A and an enzyme variant without the cellulose-binding domain (CBM. Results We studied the binding of XOSs to TrCel7A by isothermal titration calorimetry. We found that XOSs bind to TrCel7A and that the affinity increases commensurate with XOS length. The CBM, on the other hand, did not affect the affinity significantly, which suggests that XOSs may bind to the active site. Activity assays of TrCel7A clearly demonstrated the negative effect of the presence of XOSs on the turnover number. Conclusions On the basis of these binding data and a comparison of XOS inhibition of the activity of the two enzyme variants towards, respectively, soluble and insoluble substrates, we propose a competitive mechanism for XOS inhibition of TrCel7A with phosphoric swollen cellulose as a substrate.

  16. Cellulase Production from Spent Lignocellulose Hydrolysates by Recombinant Aspergillus niger▿

    Science.gov (United States)

    Alriksson, Björn; Rose, Shaunita H.; van Zyl, Willem H.; Sjöde, Anders; Nilvebrant, Nils-Olof; Jönsson, Leif J.

    2009-01-01

    A recombinant Aspergillus niger strain expressing the Hypocrea jecorina endoglucanase Cel7B was grown on spent hydrolysates (stillage) from sugarcane bagasse and spruce wood. The spent hydrolysates served as excellent growth media for the Cel7B-producing strain, A. niger D15[egI], which displayed higher endoglucanase activities in the spent hydrolysates than in standard medium with a comparable monosaccharide content (e.g., 2,100 nkat/ml in spent bagasse hydrolysate compared to 480 nkat/ml in standard glucose-based medium). In addition, A. niger D15[egI] was also able to consume or convert other lignocellulose-derived compounds, such as acetic acid, furan aldehydes, and phenolic compounds, which are recognized as inhibitors of yeast during ethanolic fermentation. The results indicate that enzymes can be produced from the stillage stream as a high-value coproduct in second-generation bioethanol plants in a way that also facilitates recirculation of process water. PMID:19251882

  17. Production of cellulolytic enzymes by fungal cultures. [Aspergillus, Trichoderma, Chaetomium, Stachybotrys, and Hypocrea

    Energy Technology Data Exchange (ETDEWEB)

    Pyc, R; Fiechter, A. Galas, E.

    1977-01-01

    Twelve fungal cultures belonging to the genera of Aspergillus, Trichoderma, Chaetomium, Stachybotrys, and Hypocrea were screened for the production of cellulolytic activity. All twelve were found to degrade xylan, avicel, and carboxymethylcellulose. More cellulolytic activity was obtained with shaken cultures than with still cultures and the addition of citrate-phosphate buffer to the media greatly depressed the levels of cellulolytic activity. Varying the composition of the mineral salts in the medium had no effect on the cellulolytic activity. The growth of Aspergillus wentii under controlled conditions in a bioreactor showed that the cellulolytic activity was not affected by the aeration rate or the type of stirrer. The rate of stirring, however, did effect the cellulolytic activity, as at lower stirring speeds considerable wall growth occurred which resulted in low levels of cellulolytic activity. Culture supernatant from Aspergillus wentii was found to hydrolyze from 30-32% of Solka-Floc and from 2-10% of corn cobs, wheat straw, and newsprint. The extensive hydrolysis of Solka-Floc indicates that with suitable treated cellulosic wastes and appropriate enzymes, appreciable amounts of sugars could be obtained.

  18. Heat inactivation kinetics of Hypocrea orientalis β-glucosidase with enhanced thermal stability by glucose.

    Science.gov (United States)

    Xu, Xin-Qi; Shi, Yan; Wu, Xiao-Bing; Zhan, Xi-Lan; Zhou, Han-Tao; Chen, Qing-Xi

    2015-11-01

    Thermal inactivation kinetics of Hypocrea orientalis β-glucosidase and effect of glucose on thermostability of the enzyme have been determined in this paper. Kinetic studies showed that the thermal inactivation was irreversible and first-order reaction. The microscopic rate constants for inactivation of free enzyme and substrate-enzyme complex were both determined, which suggested that substrates can protect β-glucosidase against thermal deactivation effectively. On the other hand, glucose was found to protect β-glucosidase from heat inactivation to remain almost whole activity below 70°C at 20mM concentration, whereas the apparent inactivation rate of BG decreased to be 0.3×10(-3)s(-1) in the presence of 5mM glucose, smaller than that of sugar-free enzyme (1.91×10(-3)s(-1)). The intrinsic fluorescence spectra results showed that glucose also had stabilizing effect on the conformation of BG against thermal denaturation. Docking simulation depicted the interaction mode between glucose and active residues of the enzyme to produce stabilizing effect. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Different Covalent Immobilizations Modulate Lipase Activities of Hypocrea pseudokoningii

    Directory of Open Access Journals (Sweden)

    Marita G. Pereira

    2017-09-01

    Full Text Available Enzyme immobilization can promote several advantages for their industrial application. In this work, a lipase from Hypocrea pseudokoningii was efficiently linked to four chemical supports: agarose activated with cyanogen bromide (CNBr, glyoxyl-agarose (GX, MANAE-agarose activated with glutaraldehyde (GA and GA-crosslinked with glutaraldehyde. Results showed a more stable lipase with both the GA-crosslinked and GA derivatives, compared to the control (CNBr, at 50 °C, 60 °C and 70 °C. Moreover, all derivatives were stabilized when incubated with organic solvents at 50%, such as ethanol, methanol, n-propanol and cyclohexane. Furthermore, lipase was highly activated (4-fold in the presence of cyclohexane. GA-crosslinked and GA derivatives were more stable than the CNBr one in the presence of organic solvents. All derivatives were able to hydrolyze sardine, açaí (Euterpe oleracea, cotton seed and grape seed oils. However, during the hydrolysis of sardine oil, GX derivative showed to be 2.3-fold more selectivity (eicosapentaenoic acid (EPA/docosahexaenoic acid (DHA ratio than the control. Additionally, the types of immobilization interfered with the lipase enantiomeric preference. Unlike the control, the other three derivatives preferably hydrolyzed the R-isomer of 2-hydroxy-4-phenylbutanoic acid ethyl ester and the S-isomer of 1-phenylethanol acetate racemic mixtures. On the other hand, GX and CNBr derivatives preferably hydrolyzed the S-isomer of butyryl-2-phenylacetic acid racemic mixture while the GA and GA-crosslink derivatives preferably hydrolyzed the R-isomer. However, all derivatives, including the control, preferably hydrolyzed the methyl mandelate S-isomer. Moreover, the derivatives could be used for eight consecutive cycles retaining more than 50% of their residual activity. This work shows the importance of immobilization as a tool to increase the lipase stability to temperature and organic solvents, thus enabling the possibility of

  20. Disruption of Trichoderma reesei cre2, encoding an ubiquitin C-terminal hydrolase, results in increased cellulase activity

    Science.gov (United States)

    2011-01-01

    Background The filamentous fungus Trichoderma reesei (Hypocrea jecorina) is an important source of cellulases for use in the textile and alternative fuel industries. To fully understand the regulation of cellulase production in T. reesei, the role of a gene known to be involved in carbon regulation in Aspergillus nidulans, but unstudied in T. reesei, was investigated. Results The T. reesei orthologue of the A. nidulans creB gene, designated cre2, was identified and shown to be functional through heterologous complementation of a creB mutation in A. nidulans. A T. reesei strain was constructed using gene disruption techniques that contained a disrupted cre2 gene. This strain, JKTR2-6, exhibited phenotypes similar to the A. nidulans creB mutant strain both in carbon catabolite repressing, and in carbon catabolite derepressing conditions. Importantly, the disruption also led to elevated cellulase levels. Conclusions These results demonstrate that cre2 is involved in cellulase expression. Since the disruption of cre2 increases the amount of cellulase activity, without severe morphological affects, targeting creB orthologues for disruption in other industrially useful filamentous fungi, such as Aspergillus oryzae, Trichoderma harzianum or Aspergillus niger may also lead to elevated hydrolytic enzyme activity in these species. PMID:22070776

  1. Implications of cellobiohydrolase glycosylation for use in biomass conversion

    Directory of Open Access Journals (Sweden)

    Decker Stephen R

    2008-05-01

    Full Text Available Abstract The cellulase producing ascomycete, Trichoderma reesei (Hypocrea jecorina, is known to secrete a range of enzymes important for ethanol production from lignocellulosic biomass. It is also widely used for the commercial scale production of industrial enzymes because of its ability to produce high titers of heterologous proteins. During the secretion process, a number of post-translational events can occur, however, that impact protein function and stability. Another ascomycete, Aspergillus niger var. awamori, is also known to produce large quantities of heterologous proteins for industry. In this study, T. reesei Cel7A, a cellobiohydrolase, was expressed in A. niger var. awamori and subjected to detailed biophysical characterization. The purified recombinant enzyme contains six times the amount of N-linked glycan than the enzyme purified from a commercial T. reesei enzyme preparation. The activities of the two enzyme forms were compared using bacterial (microcrystalline and phosphoric acid swollen (amorphous cellulose as substrates. This comparison suggested that the increased level of N-glycosylation of the recombinant Cel7A (rCel7A resulted in reduced activity and increased non-productive binding on cellulose. When treated with the N-glycosidase PNGaseF, the molecular weight of the recombinant enzyme approached that of the commercial enzyme and the activity on cellulose was improved.

  2. Sugar-binding sites on the surface of the carbohydrate-binding module of CBH I from Trichoderma reesei.

    Science.gov (United States)

    Tavagnacco, Letizia; Mason, Philip E; Schnupf, Udo; Pitici, Felicia; Zhong, Linghao; Himmel, Michael E; Crowley, Michael; Cesàro, Attilio; Brady, John W

    2011-05-01

    Molecular dynamics simulations were carried out for a system consisting of the carbohydrate-binding module (CBM) of the cellulase CBH I from Trichoderma reesei (Hypocrea jecorina) in a concentrated solution of β-D-glucopyranose, to determine whether there is any tendency for the sugar molecules to bind to the CBM. In spite of the general tendency of glucose to behave as an osmolyte, a marked tendency for the sugar molecules to bind to the protein was observed. However, the glucose molecules tended to bind only to specific sites on the protein. As expected, the hydrophobic face of the sugar molecules, comprising the axial H1, H3, and H5 aliphatic protons, tended to adhere to the flat faces of the three tyrosine side chains on the planar binding surface of the CBM. However, a significant tendency to bind to a groove-like feature on the upper surface of the CBM was also observed. These results would not be inconsistent with a model of the mechanism for this globular domain in which the cellodextrin chain being removed from the surface of crystalline cellulose passes over the upper surface of the CBM, presumably then available for hydrolysis in the active site tunnel of this processive cellulase. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. Disruption of Trichoderma reesei cre2, encoding an ubiquitin C-terminal hydrolase, results in increased cellulase activity

    Directory of Open Access Journals (Sweden)

    Denton Jai A

    2011-11-01

    Full Text Available Abstract Background The filamentous fungus Trichoderma reesei (Hypocrea jecorina is an important source of cellulases for use in the textile and alternative fuel industries. To fully understand the regulation of cellulase production in T. reesei, the role of a gene known to be involved in carbon regulation in Aspergillus nidulans, but unstudied in T. reesei, was investigated. Results The T. reesei orthologue of the A. nidulans creB gene, designated cre2, was identified and shown to be functional through heterologous complementation of a creB mutation in A. nidulans. A T. reesei strain was constructed using gene disruption techniques that contained a disrupted cre2 gene. This strain, JKTR2-6, exhibited phenotypes similar to the A. nidulans creB mutant strain both in carbon catabolite repressing, and in carbon catabolite derepressing conditions. Importantly, the disruption also led to elevated cellulase levels. Conclusions These results demonstrate that cre2 is involved in cellulase expression. Since the disruption of cre2 increases the amount of cellulase activity, without severe morphological affects, targeting creB orthologues for disruption in other industrially useful filamentous fungi, such as Aspergillus oryzae, Trichoderma harzianum or Aspergillus niger may also lead to elevated hydrolytic enzyme activity in these species.

  4. Genetic and metabolic biodiversity of Trichoderma from Colombia and adjacent neotropic regions.

    Science.gov (United States)

    Hoyos-Carvajal, Lilliana; Orduz, Sergio; Bissett, John

    2009-09-01

    The genus Trichoderma has been studied for production of enzymes and other metabolites, as well as for exploitation as effective biological control agents. The biodiversity of Trichoderma has seen relatively limited study over much of the neotropical region. In the current study we assess the biodiversity of 183 isolates from Mexico, Guatemala, Panama, Ecuador, Peru, Brazil and Colombia, using morphological, metabolic and genetic approaches. A comparatively high diversity of species was found, comprising 29 taxa: Trichoderma asperellum (60 isolates), Trichoderma atroviride (3), Trichoderma brevicompactum (5), Trichoderma crassum (3), Trichoderma erinaceum (3), Trichoderma gamsii (2), Trichoderma hamatum (2), Trichoderma harzianum (49), Trichoderma koningiopsis (6), Trichoderma longibrachiatum (3), Trichoderma ovalisporum (1), Trichoderma pubescens (2), Trichoderma rossicum (4), Trichoderma spirale (1), Trichoderma tomentosum (3), Trichoderma virens (8), Trichoderma viridescens (7) and Hypocrea jecorina (3) (anamorph: Trichoderma reesei), along with 11 currently undescribed species. T. asperellum was the prevalent species and was represented by two distinct genotypes with different metabolic profiles and habitat preferences. The second predominant species, T. harzianum, was represented by three distinct genotypes. The addition of 11 currently undescribed species is evidence of the considerable unresolved biodiversity of Trichoderma in neotropical regions. Sequencing of the internal transcribed spacer regions (ITS) of the ribosomal repeat could not differentiate some species, and taken alone gave several misidentifications in part due to the presence of nonorthologous copies of the ITS in some isolates.

  5. Identifying Beneficial Qualities of Trichoderma parareesei for Plants

    Science.gov (United States)

    Rubio, M. Belén; Quijada, Narciso M.; Pérez, Esclaudys; Domínguez, Sara; Hermosa, Rosa

    2014-01-01

    Trichoderma parareesei and Trichoderma reesei (teleomorph Hypocrea jecorina) produce cellulases and xylanases of industrial interest. Here, the anamorphic strain T6 (formerly T. reesei) has been identified as T. parareesei, showing biocontrol potential against fungal and oomycete phytopathogens and enhanced hyphal growth in the presence of tomato exudates or plant cell wall polymers in in vitro assays. A Trichoderma microarray was used to examine the transcriptomic changes in T6 at 20 h of interaction with tomato plants. Out of a total 34,138 Trichoderma probe sets deposited on the microarray, 250 showed a significant change of at least 2-fold in expression in the presence of tomato plants, with most of them being downregulated. T. parareesei T6 exerted beneficial effects on tomato plants in terms of seedling lateral root development, and in adult plants it improved defense against Botrytis cinerea and growth promotion under salt stress. Time course expression patterns (0 to 6 days) observed for defense-related genes suggest that T6 was able to prime defense responses in the tomato plants against biotic and abiotic stresses. Such responses undulated, with a maximum upregulation of the jasmonic acid (JA)/ethylene (ET)-related LOX1 and EIN2 genes and the salt tolerance SOS1 gene at 24 h and that of the salicylic acid (SA)-related PR-1 gene at 48 h after T6 inoculation. Our study demonstrates that the T. parareesei T6-tomato interaction is beneficial to both partners. PMID:24413597

  6. Accurate genotyping across variant classes and lengths using variant graphs

    DEFF Research Database (Denmark)

    Sibbesen, Jonas Andreas; Maretty, Lasse; Jensen, Jacob Malte

    2018-01-01

    of read k-mers to a graph representation of the reference and variants to efficiently perform unbiased, probabilistic genotyping across the variation spectrum. We demonstrate that BayesTyper generally provides superior variant sensitivity and genotyping accuracy relative to existing methods when used...... collecting a set of candidate variants across discovery methods, individuals and databases, and then realigning the reads to the variants and reference simultaneously. However, this realignment problem has proved computationally difficult. Here, we present a new method (BayesTyper) that uses exact alignment...... to integrate variants across discovery approaches and individuals. Finally, we demonstrate that including a ‘variation-prior’ database containing already known variants significantly improves sensitivity....

  7. Cellulase variants

    Science.gov (United States)

    Blazej, Robert; Toriello, Nicholas; Emrich, Charles; Cohen, Richard N.; Koppel, Nitzan

    2015-07-14

    This invention provides novel variant cellulolytic enzymes having improved activity and/or stability. In certain embodiments the variant cellulotyic enzymes comprise a glycoside hydrolase with or comprising a substitution at one or more positions corresponding to one or more of residues F64, A226, and/or E246 in Thermobifida fusca Cel9A enzyme. In certain embodiments the glycoside hydrolase is a variant of a family 9 glycoside hydrolase. In certain embodiments the glycoside hydrolase is a variant of a theme B family 9 glycoside hydrolase.

  8. Biology and biotechnology of Trichoderma.

    Science.gov (United States)

    Schuster, André; Schmoll, Monika

    2010-07-01

    Fungi of the genus Trichoderma are soilborne, green-spored ascomycetes that can be found all over the world. They have been studied with respect to various characteristics and applications and are known as successful colonizers of their habitats, efficiently fighting their competitors. Once established, they launch their potent degradative machinery for decomposition of the often heterogeneous substrate at hand. Therefore, distribution and phylogeny, defense mechanisms, beneficial as well as deleterious interaction with hosts, enzyme production and secretion, sexual development, and response to environmental conditions such as nutrients and light have been studied in great detail with many species of this genus, thus rendering Trichoderma one of the best studied fungi with the genome of three species currently available. Efficient biocontrol strains of the genus are being developed as promising biological fungicides, and their weaponry for this function also includes secondary metabolites with potential applications as novel antibiotics. The cellulases produced by Trichoderma reesei, the biotechnological workhorse of the genus, are important industrial products, especially with respect to production of second generation biofuels from cellulosic waste. Genetic engineering not only led to significant improvements in industrial processes but also to intriguing insights into the biology of these fungi and is now complemented by the availability of a sexual cycle in T. reesei/Hypocrea jecorina, which significantly facilitates both industrial and basic research. This review aims to give a broad overview on the qualities and versatility of the best studied Trichoderma species and to highlight intriguing findings as well as promising applications.

  9. Correlation of gene expression and protein production rate - a system wide study

    Directory of Open Access Journals (Sweden)

    Arvas Mikko

    2011-12-01

    Full Text Available Abstract Background Growth rate is a major determinant of intracellular function. However its effects can only be properly dissected with technically demanding chemostat cultivations in which it can be controlled. Recent work on Saccharomyces cerevisiae chemostat cultivations provided the first analysis on genome wide effects of growth rate. In this work we study the filamentous fungus Trichoderma reesei (Hypocrea jecorina that is an industrial protein production host known for its exceptional protein secretion capability. Interestingly, it exhibits a low growth rate protein production phenotype. Results We have used transcriptomics and proteomics to study the effect of growth rate and cell density on protein production in chemostat cultivations of T. reesei. Use of chemostat allowed control of growth rate and exact estimation of the extracellular specific protein production rate (SPPR. We find that major biosynthetic activities are all negatively correlated with SPPR. We also find that expression of many genes of secreted proteins and secondary metabolism, as well as various lineage specific, mostly unknown genes are positively correlated with SPPR. Finally, we enumerate possible regulators and regulatory mechanisms, arising from the data, for this response. Conclusions Based on these results it appears that in low growth rate protein production energy is very efficiently used primarly for protein production. Also, we propose that flux through early glycolysis or the TCA cycle is a more fundamental determining factor than growth rate for low growth rate protein production and we propose a novel eukaryotic response to this i.e. the lineage specific response (LSR.

  10. Somatic cancer variant curation and harmonization through consensus minimum variant level data

    Directory of Open Access Journals (Sweden)

    Deborah I. Ritter

    2016-11-01

    Full Text Available Abstract Background To truly achieve personalized medicine in oncology, it is critical to catalog and curate cancer sequence variants for their clinical relevance. The Somatic Working Group (WG of the Clinical Genome Resource (ClinGen, in cooperation with ClinVar and multiple cancer variant curation stakeholders, has developed a consensus set of minimal variant level data (MVLD. MVLD is a framework of standardized data elements to curate cancer variants for clinical utility. With implementation of MVLD standards, and in a working partnership with ClinVar, we aim to streamline the somatic variant curation efforts in the community and reduce redundancy and time burden for the interpretation of cancer variants in clinical practice. Methods We developed MVLD through a consensus approach by i reviewing clinical actionability interpretations from institutions participating in the WG, ii conducting extensive literature search of clinical somatic interpretation schemas, and iii survey of cancer variant web portals. A forthcoming guideline on cancer variant interpretation, from the Association of Molecular Pathology (AMP, can be incorporated into MVLD. Results Along with harmonizing standardized terminology for allele interpretive and descriptive fields that are collected by many databases, the MVLD includes unique fields for cancer variants such as Biomarker Class, Therapeutic Context and Effect. In addition, MVLD includes recommendations for controlled semantics and ontologies. The Somatic WG is collaborating with ClinVar to evaluate MVLD use for somatic variant submissions. ClinVar is an open and centralized repository where sequencing laboratories can report summary-level variant data with clinical significance, and ClinVar accepts cancer variant data. Conclusions We expect the use of the MVLD to streamline clinical interpretation of cancer variants, enhance interoperability among multiple redundant curation efforts, and increase submission of

  11. CDKL5 variants

    Science.gov (United States)

    Kalscheuer, Vera M.; Hennig, Friederike; Leonard, Helen; Downs, Jenny; Clarke, Angus; Benke, Tim A.; Armstrong, Judith; Pineda, Mercedes; Bailey, Mark E.S.; Cobb, Stuart R.

    2017-01-01

    Objective: To provide new insights into the interpretation of genetic variants in a rare neurologic disorder, CDKL5 deficiency, in the contexts of population sequencing data and an updated characterization of the CDKL5 gene. Methods: We analyzed all known potentially pathogenic CDKL5 variants by combining data from large-scale population sequencing studies with CDKL5 variants from new and all available clinical cohorts and combined this with computational methods to predict pathogenicity. Results: The study has identified several variants that can be reclassified as benign or likely benign. With the addition of novel CDKL5 variants, we confirm that pathogenic missense variants cluster in the catalytic domain of CDKL5 and reclassify a purported missense variant as having a splicing consequence. We provide further evidence that missense variants in the final 3 exons are likely to be benign and not important to disease pathology. We also describe benign splicing and nonsense variants within these exons, suggesting that isoform hCDKL5_5 is likely to have little or no neurologic significance. We also use the available data to make a preliminary estimate of minimum incidence of CDKL5 deficiency. Conclusions: These findings have implications for genetic diagnosis, providing evidence for the reclassification of specific variants previously thought to result in CDKL5 deficiency. Together, these analyses support the view that the predominant brain isoform in humans (hCDKL5_1) is crucial for normal neurodevelopment and that the catalytic domain is the primary functional domain. PMID:29264392

  12. Roles of Protein Kinase A and Adenylate Cyclase in Light-Modulated Cellulase Regulation in Trichoderma reesei

    Science.gov (United States)

    Schuster, André; Tisch, Doris; Seidl-Seiboth, Verena; Kubicek, Christian P.

    2012-01-01

    The cyclic AMP (cAMP) pathway represents a central signaling cascade with crucial functions in all organisms. Previous studies of Trichoderma reesei (anamorph of Hypocrea jecorina) suggested a function of cAMP signaling in regulation of cellulase gene expression. We were therefore interested in how the crucial components of this pathway, adenylate cyclase (ACY1) and cAMP-dependent protein kinase A (PKA), would affect cellulase gene expression. We found that both ACY1 and PKA catalytic subunit 1 (PKAC1) are involved in regulation of vegetative growth but are not essential for sexual development. Interestingly, our results showed considerably increased transcript abundance of cellulase genes in darkness compared to light (light responsiveness) upon growth on lactose. This effect is strongly enhanced in mutant strains lacking PKAC1 or ACY1. Comparison to the wild type showed that ACY1 has a consistently positive effect on cellulase gene expression in light and darkness, while PKAC1 influences transcript levels of cellulase genes positively in light but negatively in darkness. A function of PKAC1 in light-modulated cellulase gene regulation is also reflected by altered complex formation within the cel6a/cbh2 promoter in light and darkness and in the absence of pkac1. Analysis of transcript levels of cellulase regulator genes indicates that the regulatory output of the cAMP pathway may be established via adjustment of XYR1 abundance. Consequently, both adenylate cyclase and protein kinase A are involved in light-modulated cellulase gene expression in T. reesei and have a dampening effect on the light responsiveness of this process. PMID:22286997

  13. Product Variant Master as a Means to Handle Variant Design

    DEFF Research Database (Denmark)

    Hildre, Hans Petter; Mortensen, Niels Henrik; Andreasen, Mogens Myrup

    1996-01-01

    be implemented in the CAD system I-DEAS. A precondition for high degree of computer support is identification of a product variant master from which new variants can be derived. This class platform defines how a product build up fit certain production methods and rules governing determination of modules...

  14. Hairy cell leukemia-variant

    International Nuclear Information System (INIS)

    Quadri, Mohammad I.; Al-Sheikh, Iman H.

    2001-01-01

    Hairy cell leukaemia variant is a very rare chronic lymphoproliferative disorder and is closely related to hairy cell leukemia. We hereby describe a case of hairy cell leukaemia variant for the first time in Saudi Arabia. An elderly Saudi man presented with pallor, massive splenomegaly, and moderate hepatomegaly. Hemoglobin was 7.7 g/dl, Platelets were 134 x109/l and white blood count was 140x10 9/l with 97% being abnormal lymphoid cells with cytoplasmic projections. The morphology, cytochemistry, and immunophenotype of the lymphoid cells were classical of hairy cell leukaemia variant. The bone marrow was easily aspirated and findings were consistent with hairy cell leukaemia variant. (author)

  15. Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic

    DEFF Research Database (Denmark)

    Ahlborn, Lise B; Dandanell, Mette; Steffensen, Ane Y

    2015-01-01

    by functional analysis at the protein level. Results from a validated mini-gene splicing assay indicated that nine BRCA1 variants resulted in splicing aberrations leading to truncated transcripts and thus can be considered pathogenic (c.4987A>T/p.Met1663Leu, c.4988T>A/p.Met1663Lys, c.5072C>T/p.Thr1691Ile, c......Pathogenic germline mutations in the BRCA1 gene predispose carriers to early onset breast and ovarian cancer. Clinical genetic screening of BRCA1 often reveals variants with uncertain clinical significance, complicating patient and family management. Therefore, functional examinations are urgently...... needed to classify whether these uncertain variants are pathogenic or benign. In this study, we investigated 14 BRCA1 variants by in silico splicing analysis and mini-gene splicing assay. All 14 alterations were missense variants located within the BRCT domain of BRCA1 and had previously been examined...

  16. A rabies virus vampire bat variant shows increased neuroinvasiveness in mice when compared to a carnivore variant.

    Science.gov (United States)

    Mesquita, Leonardo Pereira; Gamon, Thais Helena Martins; Cuevas, Silvia Elena Campusano; Asano, Karen Miyuki; Fahl, Willian de Oliveira; Iamamoto, Keila; Scheffer, Karin Correa; Achkar, Samira Maria; Zanatto, Dennis Albert; Mori, Cláudia Madalena Cabrera; Maiorka, Paulo César; Mori, Enio

    2017-12-01

    Rabies is one of the most important zoonotic diseases and is caused by several rabies virus (RABV) variants. These variants can exhibit differences in neurovirulence, and few studies have attempted to evaluate the neuroinvasiveness of variants derived from vampire bats and wild carnivores. The aim of this study was to evaluate the neuropathogenesis of infection with two Brazilian RABV street variants (variant 3 and crab-eating fox) in mice. BALB/c mice were inoculated with RABV through the footpad, with the 50% mouse lethal dose (LD 50 ) determined by intracranial inoculation. The morbidity of rabies in mice infected with variant 3 and the crab-eating fox strain was 100% and 50%, respectively, with an incubation period of 7 and 6 days post-inoculation (dpi), respectively. The clinical disease in mice was similar with both strains, and it was characterized initially by weight loss, ruffled fur, hunched posture, and hind limb paralysis progressing to quadriplegia and recumbency at 9 to 12 dpi. Histological lesions within the central nervous system (CNS) characterized by nonsuppurative encephalomyelitis with neuronal degeneration and necrosis were observed in mice infected with variant 3 and those infected with the crab-eating fox variant. However, lesions and the presence of RABV antigen, were more widespread within the CNS of variant-3-infected mice, whereas in crab-eating fox-variant-infected mice, RABV antigens were more restricted to caudal areas of the CNS, such as the spinal cord and brainstem. In conclusion, the results shown here demonstrate that the RABV vampire bat strain (variant 3) has a higher potential for neuroinvasiveness than the carnivore variant.

  17. Comparative genome sequence analysis underscores mycoparasitism as the ancestral life style of Trichoderma

    OpenAIRE

    Kubicek, Christian P.; Herrera-Estrella, Alfredo; Seidl-Seiboth, Verena; Martinez, Diego A.; Druzhinina, Irina S.; Thon, Michael; Zeilinger, Susanne; Casas-Flores, Sergio; Horwitz, Benjamin A.; Mukherjee, Prasun K.; Mukherjee, Mala; Kredics, László; Alcaraz, Luis D.; Aerts, Andrea; Antal, Zsuzsanna

    2011-01-01

    Background Mycoparasitism, a lifestyle where one fungus is parasitic on another fungus, has special relevance when the prey is a plant pathogen, providing a strategy for biological control of pests for plant protection. Probably, the most studied biocontrol agents are species of the genus Hypocrea/Trichoderma. Results Here we report an analysis of the genome sequences of the two biocontrol species Trichoderma atroviride (teleomorph Hypocrea atroviridis) and Trichoderma virens (formerly Gliocl...

  18. The predominant molecular state of bound enzyme determines the strength and type of product inhibition in the hydrolysis of recalcitrant polysaccharides by processive enzymes.

    Science.gov (United States)

    Kuusk, Silja; Sørlie, Morten; Väljamäe, Priit

    2015-05-01

    Processive enzymes are major components of the efficient enzyme systems that are responsible for the degradation of the recalcitrant polysaccharides cellulose and chitin. Despite intensive research, there is no consensus on which step is rate-limiting for these enzymes. Here, we performed a comparative study of two well characterized enzymes, the cellobiohydrolase Cel7A from Hypocrea jecorina and the chitinase ChiA from Serratia marcescens. Both enzymes were inhibited by their disaccharide product, namely chitobiose for ChiA and cellobiose for Cel7A. The products behaved as noncompetitive inhibitors according to studies using the (14)C-labeled crystalline polymeric substrates (14)C chitin nanowhiskers and (14)C-labeled bacterial microcrystalline cellulose for ChiA and Cel7A, respectively. The resulting observed Ki (obs) values were 0.45 ± 0.08 mm for ChiA and 0.17 ± 0.02 mm for Cel7A. However, in contrast to ChiA, the Ki (obs) of Cel7A was an order of magnitude higher than the true Ki value governed by the thermodynamic stability of the enzyme-inhibitor complex. Theoretical analysis of product inhibition suggested that the inhibition strength and pattern can be accounted for by assuming different rate-limiting steps for ChiA and Cel7A. Measuring the population of enzymes whose active site was occupied by a polymer chain revealed that Cel7A was bound predominantly via its active site. Conversely, the active-site-mediated binding of ChiA was slow, and most ChiA exhibited a free active site, even when the substrate concentration was saturating for the activity. Collectively, our data suggest that complexation with the polymer chain is rate-limiting for ChiA, whereas Cel7A is limited by dissociation. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. Unravelling the molecular basis for light modulated cellulase gene expression - the role of photoreceptors in Neurospora crassa

    Science.gov (United States)

    2012-01-01

    Background Light represents an important environmental cue, which exerts considerable influence on the metabolism of fungi. Studies with the biotechnological fungal workhorse Trichoderma reesei (Hypocrea jecorina) have revealed an interconnection between transcriptional regulation of cellulolytic enzymes and the light response. Neurospora crassa has been used as a model organism to study light and circadian rhythm biology. We therefore investigated whether light also regulates transcriptional regulation of cellulolytic enzymes in N. crassa. Results We show that the N. crassa photoreceptor genes wc-1, wc-2 and vvd are involved in regulation of cellulase gene expression, indicating that this phenomenon is conserved among filamentous fungi. The negative effect of VVD on production of cellulolytic enzymes is thereby accomplished by its role in photoadaptation and hence its function in White collar complex (WCC) formation. In contrast, the induction of vvd expression by the WCC does not seem to be crucial in this process. Additionally, we found that WC-1 and WC-2 not only act as a complex, but also have individual functions upon growth on cellulose. Conclusions Genome wide transcriptome analysis of photoreceptor mutants and evaluation of results by analysis of mutant strains identified several candidate genes likely to play a role in light modulated cellulase gene expression. Genes with functions in amino acid metabolism, glycogen metabolism, energy supply and protein folding are enriched among genes with decreased expression levels in the wc-1 and wc-2 mutants. The ability to properly respond to amino acid starvation, i. e. up-regulation of the cross pathway control protein cpc-1, was found to be beneficial for cellulase gene expression. Our results further suggest a contribution of oxidative depolymerization of cellulose to plant cell wall degradation in N. crassa. PMID:22462823

  20. Structural characterization of a unique marine animal family 7 cellobiohydrolase suggests a mechanism of cellulase salt tolerance.

    Science.gov (United States)

    Kern, Marcelo; McGeehan, John E; Streeter, Simon D; Martin, Richard N A; Besser, Katrin; Elias, Luisa; Eborall, Will; Malyon, Graham P; Payne, Christina M; Himmel, Michael E; Schnorr, Kirk; Beckham, Gregg T; Cragg, Simon M; Bruce, Neil C; McQueen-Mason, Simon J

    2013-06-18

    Nature uses a diversity of glycoside hydrolase (GH) enzymes to convert polysaccharides to sugars. As lignocellulosic biomass deconstruction for biofuel production remains costly, natural GH diversity offers a starting point for developing industrial enzymes, and fungal GH family 7 (GH7) cellobiohydrolases, in particular, provide significant hydrolytic potential in industrial mixtures. Recently, GH7 enzymes have been found in other kingdoms of life besides fungi, including in animals and protists. Here, we describe the in vivo spatial expression distribution, properties, and structure of a unique endogenous GH7 cellulase from an animal, the marine wood borer Limnoria quadripunctata (LqCel7B). RT-quantitative PCR and Western blot studies show that LqCel7B is expressed in the hepatopancreas and secreted into the gut for wood degradation. We produced recombinant LqCel7B, with which we demonstrate that LqCel7B is a cellobiohydrolase and obtained four high-resolution crystal structures. Based on a crystallographic and computational comparison of LqCel7B to the well-characterized Hypocrea jecorina GH7 cellobiohydrolase, LqCel7B exhibits an extended substrate-binding motif at the tunnel entrance, which may aid in substrate acquisition and processivity. Interestingly, LqCel7B exhibits striking surface charges relative to fungal GH7 enzymes, which likely results from evolution in marine environments. We demonstrate that LqCel7B stability and activity remain unchanged, or increase at high salt concentration, and that the L. quadripunctata GH mixture generally contains cellulolytic enzymes with highly acidic surface charge compared with enzymes derived from terrestrial microbes. Overall, this study suggests that marine cellulases offer significant potential for utilization in high-solids industrial biomass conversion processes.

  1. Variants of Moreau's sweeping process

    International Nuclear Information System (INIS)

    Siddiqi, A.H.; Manchanda, P.

    2001-07-01

    In this paper we prove the existence and uniqueness of two variants of Moreau's sweeping process -u'(t) is an element of Nc (t) (u(t)), where in one variant we replace u(t) by u'(t) in the right-hand side of the inclusion and in the second variant u'(t) and u(t) are respectively replaced by u''(t) and u'(t). (author)

  2. Characterization of form variants of Xenorhabdus luminescens.

    Science.gov (United States)

    Gerritsen, L J; de Raay, G; Smits, P H

    1992-01-01

    From Xenorhabdus luminescens XE-87.3 four variants were isolated. One, which produced a red pigment and antibiotics, was luminescent, and could take up dye from culture media, was considered the primary form (XE-red). A pink-pigmented variant (XE-pink) differed from the primary form only in pigmentation and uptake of dye. Of the two other variants, one produced a yellow pigment and fewer antibiotics (XE-yellow), while the other did not produce a pigment or antibiotics (XE-white). Both were less luminescent, did not take up dye, and had small cell and colony sizes. These two variants were very unstable and shifted to the primary form after 3 to 5 days. It was not possible to separate the primary form and the white variant completely; subcultures of one colony always contained a few colonies of the other variant. The white variant was also found in several other X. luminescens strains. DNA fingerprints showed that all four variants are genetically identical and are therefore derivatives of the same parent. Protein patterns revealed a few differences among the four variants. None of the variants could be considered the secondary form. The pathogenicity of the variants decreased in the following order: XE-red, XE-pink, XE-yellow, and XE-white. The mechanism and function of this variability are discussed. Images PMID:1622273

  3. Random Plant Viral Variants Attain Temporal Advantages During Systemic Infections and in Turn Resist other Variants of the Same Virus.

    Science.gov (United States)

    Zhang, Xiao-Feng; Guo, Jiangbo; Zhang, Xiuchun; Meulia, Tea; Paul, Pierce; Madden, Laurence V; Li, Dawei; Qu, Feng

    2015-10-20

    Infection of plants with viruses containing multiple variants frequently leads to dominance by a few random variants in the systemically infected leaves (SLs), for which a plausible explanation is lacking. We show here that SL dominance by a given viral variant is adequately explained by its fortuitous lead in systemic spread, coupled with its resistance to superinfection by other variants. We analyzed the fate of a multi-variant turnip crinkle virus (TCV) population in Arabidopsis and N. benthamiana plants. Both wild-type and RNA silencing-defective plants displayed a similar pattern of random dominance by a few variant genotypes, thus discounting a prominent role for RNA silencing. When introduced to plants sequentially as two subpopulations, a twelve-hour head-start was sufficient for the first set to dominate. Finally, SLs of TCV-infected plants became highly resistant to secondary invasions of another TCV variant. We propose that random distribution of variant foci on inoculated leaves allows different variants to lead systemic movement in different plants. The leading variants then colonize large areas of SLs, and resist the superinfection of lagging variants in the same areas. In conclusion, superinfection resistance is the primary driver of random enrichment of viral variants in systemically infected plants.

  4. Semantic prioritization of novel causative genomic variants

    KAUST Repository

    Boudellioua, Imene

    2017-04-17

    Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

  5. Semantic prioritization of novel causative genomic variants

    KAUST Repository

    Boudellioua, Imene; Mohamad Razali, Rozaimi; Kulmanov, Maxat; Hashish, Yasmeen; Bajic, Vladimir B.; Goncalves-Serra, Eva; Schoenmakers, Nadia; Gkoutos, Georgios V.; Schofield, Paul N.; Hoehndorf, Robert

    2017-01-01

    Discriminating the causative disease variant(s) for individuals with inherited or de novo mutations presents one of the main challenges faced by the clinical genetics community today. Computational approaches for variant prioritization include machine learning methods utilizing a large number of features, including molecular information, interaction networks, or phenotypes. Here, we demonstrate the PhenomeNET Variant Predictor (PVP) system that exploits semantic technologies and automated reasoning over genotype-phenotype relations to filter and prioritize variants in whole exome and whole genome sequencing datasets. We demonstrate the performance of PVP in identifying causative variants on a large number of synthetic whole exome and whole genome sequences, covering a wide range of diseases and syndromes. In a retrospective study, we further illustrate the application of PVP for the interpretation of whole exome sequencing data in patients suffering from congenital hypothyroidism. We find that PVP accurately identifies causative variants in whole exome and whole genome sequencing datasets and provides a powerful resource for the discovery of causal variants.

  6. Swine Influenza/Variant Influenza Viruses

    Science.gov (United States)

    ... Address What's this? Submit What's this? Submit Button Influenza Types Seasonal Avian Swine Variant Pandemic Other Information on Swine Influenza/Variant Influenza Virus Language: English (US) Español Recommend ...

  7. Beta-glucosidase variants and polynucleotides encoding same

    Science.gov (United States)

    Wogulis, Mark; Harris, Paul; Osborn, David

    2017-06-27

    The present invention relates to beta-glucosidase variants, e.g. beta-glucosidase variants of a parent Family GH3A beta-glucosidase from Aspergillus fumigatus. The present invention also relates to polynucleotides encoding the beta-glucosidase variants; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the beta-glucosidase variants.

  8. Taxon-specific metagenomics of Trichoderma reveals a narrow community of opportunistic species that regulate each other’s development

    Science.gov (United States)

    Friedl, Martina A.

    2012-01-01

    In this paper, we report on the in situ diversity of the mycotrophic fungus Trichoderma (teleomorph Hypocrea, Ascomycota, Dikarya) revealed by a taxon-specific metagenomic approach. We designed a set of genus-specific internal transcribed spacer (ITS)1 and ITS2 rRNA primers and constructed a clone library containing 411 molecular operational taxonomic units (MOTUs). The overall species composition in the soil of the two distinct ecosystems in the Danube floodplain consisted of 15 known species and two potentially novel taxa. The latter taxa accounted for only 1.5 % of all MOTUs, suggesting that almost no hidden or uncultivable Hypocrea/Trichoderma species are present at least in these temperate forest soils. The species were unevenly distributed in vertical soil profiles although no universal factors controlling the distribution of all of them (chemical soil properties, vegetation type and affinity to rhizosphere) were revealed. In vitro experiments simulating infrageneric interactions between the pairs of species that were detected in the same soil horizon showed a broad spectrum of reactions from very strong competition over neutral coexistence to the pronounced synergism. Our data suggest that only a relatively small portion of Hypocrea/Trichoderma species is adapted to soil as a habitat and that the interaction between these species should be considered in a screening for Hypocrea/Trichoderma as an agent(s) of biological control of pests. PMID:22075025

  9. Congenital anomalies and normal skeletal variants

    International Nuclear Information System (INIS)

    Guebert, G.M.; Yochum, T.R.; Rowe, L.J.

    1987-01-01

    Congenital anomalies and normal skeletal variants are a common occurrence in clinical practice. In this chapter a large number of skeletal anomalies of the spine and pelvis are reviewed. Some of the more common skeletal anomalies of the extremities are also presented. The second section of this chapter deals with normal skeletal variants. Some of these variants may simulate certain disease processes. In some instances there are no clear-cut distinctions between skeletal variants and anomalies; therefore, there may be some overlap of material. The congenital anomalies are presented initially with accompanying text, photos, and references, beginning with the skull and proceeding caudally through the spine to then include the pelvis and extremities. The normal skeletal variants section is presented in an anatomical atlas format without text or references

  10. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

    Directory of Open Access Journals (Sweden)

    Mengmeng Du

    Full Text Available Genome-wide association studies (GWAS have identified many common single nucleotide polymorphisms (SNPs associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs. We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33. We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s.

  11. Annotating pathogenic non-coding variants in genic regions.

    Science.gov (United States)

    Gelfman, Sahar; Wang, Quanli; McSweeney, K Melodi; Ren, Zhong; La Carpia, Francesca; Halvorsen, Matt; Schoch, Kelly; Ratzon, Fanni; Heinzen, Erin L; Boland, Michael J; Petrovski, Slavé; Goldstein, David B

    2017-08-09

    Identifying the underlying causes of disease requires accurate interpretation of genetic variants. Current methods ineffectively capture pathogenic non-coding variants in genic regions, resulting in overlooking synonymous and intronic variants when searching for disease risk. Here we present the Transcript-inferred Pathogenicity (TraP) score, which uses sequence context alterations to reliably identify non-coding variation that causes disease. High TraP scores single out extremely rare variants with lower minor allele frequencies than missense variants. TraP accurately distinguishes known pathogenic and benign variants in synonymous (AUC = 0.88) and intronic (AUC = 0.83) public datasets, dismissing benign variants with exceptionally high specificity. TraP analysis of 843 exomes from epilepsy family trios identifies synonymous variants in known epilepsy genes, thus pinpointing risk factors of disease from non-coding sequence data. TraP outperforms leading methods in identifying non-coding variants that are pathogenic and is therefore a valuable tool for use in gene discovery and the interpretation of personal genomes.While non-coding synonymous and intronic variants are often not under strong selective constraint, they can be pathogenic through affecting splicing or transcription. Here, the authors develop a score that uses sequence context alterations to predict pathogenicity of synonymous and non-coding genetic variants, and provide a web server of pre-computed scores.

  12. Histone variants and lipid metabolism

    NARCIS (Netherlands)

    Borghesan, Michela; Mazzoccoli, Gianluigi; Sheedfar, Fareeba; Oben, Jude; Pazienza, Valerio; Vinciguerra, Manlio

    2014-01-01

    Within nucleosomes, canonical histones package the genome, but they can be opportunely replaced with histone variants. The incorporation of histone variants into the nucleosome is a chief cellular strategy to regulate transcription and cellular metabolism. In pathological terms, cellular steatosis

  13. CLEVER: Clique-Enumerating Variant Finder

    NARCIS (Netherlands)

    Marschall, T.; Costa, I.; Canzar, S.; bauer, m; Klau, G.W.; Schliep, A.; Schönhuth, A.

    2012-01-01

    Motivation: Next-generation sequencing techniques have facilitated a large-scale analysis of human genetic variation. Despite the advances in sequencing speed, the computational discovery of structural variants is not yet standard. It is likely that many variants have remained undiscovered in most

  14. The curation of genetic variants: difficulties and possible solutions.

    Science.gov (United States)

    Pandey, Kapil Raj; Maden, Narendra; Poudel, Barsha; Pradhananga, Sailendra; Sharma, Amit Kumar

    2012-12-01

    The curation of genetic variants from biomedical articles is required for various clinical and research purposes. Nowadays, establishment of variant databases that include overall information about variants is becoming quite popular. These databases have immense utility, serving as a user-friendly information storehouse of variants for information seekers. While manual curation is the gold standard method for curation of variants, it can turn out to be time-consuming on a large scale thus necessitating the need for automation. Curation of variants described in biomedical literature may not be straightforward mainly due to various nomenclature and expression issues. Though current trends in paper writing on variants is inclined to the standard nomenclature such that variants can easily be retrieved, we have a massive store of variants in the literature that are present as non-standard names and the online search engines that are predominantly used may not be capable of finding them. For effective curation of variants, knowledge about the overall process of curation, nature and types of difficulties in curation, and ways to tackle the difficulties during the task are crucial. Only by effective curation, can variants be correctly interpreted. This paper presents the process and difficulties of curation of genetic variants with possible solutions and suggestions from our work experience in the field including literature support. The paper also highlights aspects of interpretation of genetic variants and the importance of writing papers on variants following standard and retrievable methods. Copyright © 2012. Published by Elsevier Ltd.

  15. Word Variant Identification in Old French

    Directory of Open Access Journals (Sweden)

    Peter Willett

    1997-01-01

    Full Text Available Increasing numbers of historical texts are available in machine-readable form, which retain the original spelling, which can be very different from the modern-day equivalents due to the natural evolution of a language, and because the concept of standardisation in spelling is comparatively modern. Among medieval vernacular writers, the same word could be spelled in different ways and the same author (or scribe might even use several alternative spellings in the same passage. Thus, we do not know,a priori, how many variant forms of a particular word there are in such texts, let alone what these variants might be. Searching on the modern equivalent, or even the commonest historical variant, of a particular word may thus fail to retrieve an appreciable number of occurrences unless the searcher already has an extensive knowledge of the language of the documents. Moreover, even specialist scholars may be unaware of some idiosyncratic variants. Here, we consider the use of computer methods to retrieve variant historical spellings.

  16. TREM2 Variants in Alzheimer's Disease

    Science.gov (United States)

    Guerreiro, Rita; Wojtas, Aleksandra; Bras, Jose; Carrasquillo, Minerva; Rogaeva, Ekaterina; Majounie, Elisa; Cruchaga, Carlos; Sassi, Celeste; Kauwe, John S.K.; Younkin, Steven; Hazrati, Lilinaz; Collinge, John; Pocock, Jennifer; Lashley, Tammaryn; Williams, Julie; Lambert, Jean-Charles; Amouyel, Philippe; Goate, Alison; Rademakers, Rosa; Morgan, Kevin; Powell, John; St. George-Hyslop, Peter; Singleton, Andrew; Hardy, John

    2013-01-01

    BACKGROUND Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P = 0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.) PMID:23150934

  17. Combined analyses of 20 common obesity susceptibility variants

    DEFF Research Database (Denmark)

    Sandholt, Camilla Helene; Sparsø, Thomas; Grarup, Niels

    2010-01-01

    Genome-wide association studies and linkage studies have identified 20 validated genetic variants associated with obesity and/or related phenotypes. The variants are common, and they individually exhibit small-to-modest effect sizes.......Genome-wide association studies and linkage studies have identified 20 validated genetic variants associated with obesity and/or related phenotypes. The variants are common, and they individually exhibit small-to-modest effect sizes....

  18. Variant Review with the Integrative Genomics Viewer.

    Science.gov (United States)

    Robinson, James T; Thorvaldsdóttir, Helga; Wenger, Aaron M; Zehir, Ahmet; Mesirov, Jill P

    2017-11-01

    Manual review of aligned reads for confirmation and interpretation of variant calls is an important step in many variant calling pipelines for next-generation sequencing (NGS) data. Visual inspection can greatly increase the confidence in calls, reduce the risk of false positives, and help characterize complex events. The Integrative Genomics Viewer (IGV) was one of the first tools to provide NGS data visualization, and it currently provides a rich set of tools for inspection, validation, and interpretation of NGS datasets, as well as other types of genomic data. Here, we present a short overview of IGV's variant review features for both single-nucleotide variants and structural variants, with examples from both cancer and germline datasets. IGV is freely available at https://www.igv.org Cancer Res; 77(21); e31-34. ©2017 AACR . ©2017 American Association for Cancer Research.

  19. Germline Variants of Prostate Cancer in Japanese Families.

    Directory of Open Access Journals (Sweden)

    Takahide Hayano

    Full Text Available Prostate cancer (PC is the second most common cancer in men. Family history is the major risk factor for PC. Only two susceptibility genes were identified in PC, BRCA2 and HOXB13. A comprehensive search of germline variants for patients with PC has not been reported in Japanese families. In this study, we conducted exome sequencing followed by Sanger sequencing to explore responsible germline variants in 140 Japanese patients with PC from 66 families. In addition to known susceptibility genes, BRCA2 and HOXB13, we identified TRRAP variants in a mutually exclusive manner in seven large PC families (three or four patients per family. We also found shared variants of BRCA2, HOXB13, and TRRAP from 59 additional small PC families (two patients per family. We identified two deleterious HOXB13 variants (F127C and G132E. Further exploration of the shared variants in rest of the families revealed deleterious variants of the so-called cancer genes (ATP1A1, BRIP1, FANCA, FGFR3, FLT3, HOXD11, MUTYH, PDGFRA, SMARCA4, and TCF3. The germline variant profile provides a new insight to clarify the genetic etiology and heterogeneity of PC among Japanese men.

  20. Detecting rare variants in case-parents association studies.

    Directory of Open Access Journals (Sweden)

    Kuang-Fu Cheng

    Full Text Available Despite the success of genome-wide association studies (GWASs in detecting common variants (minor allele frequency ≥0.05 many suggested that rare variants also contribute to the genetic architecture of diseases. Recently, researchers demonstrated that rare variants can show a strong stratification which may not be corrected by using existing methods. In this paper, we focus on a case-parents study and consider methods for testing group-wise association between multiple rare (and common variants in a gene region and a disease. All tests depend on the numbers of transmitted mutant alleles from parents to their diseased children across variants and hence they are robust to the effect of population stratification. We use extensive simulation studies to compare the performance of four competing tests: the largest single-variant transmission disequilibrium test (TDT, multivariable test, combined TDT, and a likelihood ratio test based on a random-effects model. We find that the likelihood ratio test is most powerful in a wide range of settings and there is no negative impact to its power performance when common variants are also included in the analysis. If deleterious and protective variants are simultaneously analyzed, the likelihood ratio test was generally insensitive to the effect directionality, unless the effects are extremely inconsistent in one direction.

  1. Variants of glycoside hydrolases

    Science.gov (United States)

    Teter, Sarah [Davis, CA; Ward, Connie [Hamilton, MT; Cherry, Joel [Davis, CA; Jones, Aubrey [Davis, CA; Harris, Paul [Carnation, WA; Yi, Jung [Sacramento, CA

    2011-04-26

    The present invention relates to variants of a parent glycoside hydrolase, comprising a substitution at one or more positions corresponding to positions 21, 94, 157, 205, 206, 247, 337, 350, 373, 383, 438, 455, 467, and 486 of amino acids 1 to 513 of SEQ ID NO: 2, and optionally further comprising a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2 a substitution at one or more positions corresponding to positions 8, 22, 41, 49, 57, 113, 193, 196, 226, 227, 246, 251, 255, 259, 301, 356, 371, 411, and 462 of amino acids 1 to 513 of SEQ ID NO: 2, wherein the variants have glycoside hydrolase activity. The present invention also relates to nucleotide sequences encoding the variant glycoside hydrolases and to nucleic acid constructs, vectors, and host cells comprising the nucleotide sequences.

  2. Local binary patterns new variants and applications

    CERN Document Server

    Jain, Lakhmi; Nanni, Loris; Lumini, Alessandra

    2014-01-01

    This book introduces Local Binary Patterns (LBP), arguably one of the most powerful texture descriptors, and LBP variants. This volume provides the latest reviews of the literature and a presentation of some of the best LBP variants by researchers at the forefront of textual analysis research and research on LBP descriptors and variants. The value of LBP variants is illustrated with reported experiments using many databases representing a diversity of computer vision applications in medicine, biometrics, and other areas. There is also a chapter that provides an excellent theoretical foundation for texture analysis and LBP in particular. A special section focuses on LBP and LBP variants in the area of face recognition, including thermal face recognition. This book will be of value to anyone already in the field as well as to those interested in learning more about this powerful family of texture descriptors.

  3. Variant Creutzfeldt-Jakob Disease (vCJD)

    Science.gov (United States)

    ... Form Controls Cancel Submit Search the CDC Variant Creutzfeldt-Jakob Disease (vCJD) Note: Javascript is disabled or is not ... gov . Recommend on Facebook Tweet Share Compartir Variant Creutzfeldt-Jakob disease (vCJD) is a prion disease that was first ...

  4. Population structure analysis using rare and common functional variants

    Directory of Open Access Journals (Sweden)

    Ding Lili

    2011-11-01

    Full Text Available Abstract Next-generation sequencing technologies now make it possible to genotype and measure hundreds of thousands of rare genetic variations in individuals across the genome. Characterization of high-density genetic variation facilitates control of population genetic structure on a finer scale before large-scale genotyping in disease genetics studies. Population structure is a well-known, prevalent, and important factor in common variant genetic studies, but its relevance in rare variants is unclear. We perform an extensive population structure analysis using common and rare functional variants from the Genetic Analysis Workshop 17 mini-exome sequence. The analysis based on common functional variants required 388 principal components to account for 90% of the variation in population structure. However, an analysis based on rare variants required 532 significant principal components to account for similar levels of variation. Using rare variants, we detected fine-scale substructure beyond the population structure identified using common functional variants. Our results show that the level of population structure embedded in rare variant data is different from the level embedded in common variant data and that correcting for population structure is only as good as the level one wishes to correct.

  5. Three-dimensional spatial analysis of missense variants in RTEL1 identifies pathogenic variants in patients with Familial Interstitial Pneumonia.

    Science.gov (United States)

    Sivley, R Michael; Sheehan, Jonathan H; Kropski, Jonathan A; Cogan, Joy; Blackwell, Timothy S; Phillips, John A; Bush, William S; Meiler, Jens; Capra, John A

    2018-01-23

    Next-generation sequencing of individuals with genetic diseases often detects candidate rare variants in numerous genes, but determining which are causal remains challenging. We hypothesized that the spatial distribution of missense variants in protein structures contains information about function and pathogenicity that can help prioritize variants of unknown significance (VUS) and elucidate the structural mechanisms leading to disease. To illustrate this approach in a clinical application, we analyzed 13 candidate missense variants in regulator of telomere elongation helicase 1 (RTEL1) identified in patients with Familial Interstitial Pneumonia (FIP). We curated pathogenic and neutral RTEL1 variants from the literature and public databases. We then used homology modeling to construct a 3D structural model of RTEL1 and mapped known variants into this structure. We next developed a pathogenicity prediction algorithm based on proximity to known disease causing and neutral variants and evaluated its performance with leave-one-out cross-validation. We further validated our predictions with segregation analyses, telomere lengths, and mutagenesis data from the homologous XPD protein. Our algorithm for classifying RTEL1 VUS based on spatial proximity to pathogenic and neutral variation accurately distinguished 7 known pathogenic from 29 neutral variants (ROC AUC = 0.85) in the N-terminal domains of RTEL1. Pathogenic proximity scores were also significantly correlated with effects on ATPase activity (Pearson r = -0.65, p = 0.0004) in XPD, a related helicase. Applying the algorithm to 13 VUS identified from sequencing of RTEL1 from patients predicted five out of six disease-segregating VUS to be pathogenic. We provide structural hypotheses regarding how these mutations may disrupt RTEL1 ATPase and helicase function. Spatial analysis of missense variation accurately classified candidate VUS in RTEL1 and suggests how such variants cause disease. Incorporating

  6. Data-variant kernel analysis

    CERN Document Server

    Motai, Yuichi

    2015-01-01

    Describes and discusses the variants of kernel analysis methods for data types that have been intensely studied in recent years This book covers kernel analysis topics ranging from the fundamental theory of kernel functions to its applications. The book surveys the current status, popular trends, and developments in kernel analysis studies. The author discusses multiple kernel learning algorithms and how to choose the appropriate kernels during the learning phase. Data-Variant Kernel Analysis is a new pattern analysis framework for different types of data configurations. The chapters include

  7. Combinations of Genetic Variants Occurring Exclusively in Patients

    Directory of Open Access Journals (Sweden)

    Erling Mellerup

    Full Text Available In studies of polygenic disorders, scanning the genetic variants can be used to identify variant combinations. Combinations that are exclusively found in patients can be separated from those combinations occurring in control persons. Statistical analyses can be performed to determine whether the combinations that occur exclusively among patients are significantly associated with the investigated disorder. This research strategy has been applied in materials from various polygenic disorders, identifying clusters of patient-specific genetic variant combinations that are significant associated with the investigated disorders. Combinations from these clusters are found in the genomes of up to 55% of investigated patients, and are not present in the genomes of any control persons. Keywords: Genetic variants, Polygenic disorder, Combinations of genetic variants, Patient-specific combinations

  8. Determination of uranium by luminescent method (tablet variant)

    International Nuclear Information System (INIS)

    Sergeev, A.N.; Yufa, B.Ya.

    1985-01-01

    A new tablet variant of luminescent determination of uranium in rocks is developed. The analytical process includes the following operations: sample decomposition, uranium separation from luminescence quencher impurities, preparation of luminescent sample (tablet), photometry of the tablet. The method has two variants developed: the first one is characterized by a more hard decomposition, sample mass being 0.2 g; the second variant has a better detection limit (5x10 -6 %), the sample mass being 0.2-1 g. Procedures of the sample preparation for both variants of analysis are described

  9. NMNAT1 variants cause cone and cone-rod dystrophy.

    Science.gov (United States)

    Nash, Benjamin M; Symes, Richard; Goel, Himanshu; Dinger, Marcel E; Bennetts, Bruce; Grigg, John R; Jamieson, Robyn V

    2018-03-01

    Cone and cone-rod dystrophies (CD and CRD, respectively) are degenerative retinal diseases that predominantly affect the cone photoreceptors. The underlying disease gene is not known in approximately 75% of autosomal recessive cases. Variants in NMNAT1 cause a severe, early-onset retinal dystrophy called Leber congenital amaurosis (LCA). We report two patients where clinical phenotyping indicated diagnoses of CD and CRD, respectively. NMNAT1 variants were identified, with Case 1 showing an extremely rare homozygous variant c.[271G > A] p.(Glu91Lys) and Case 2 compound heterozygous variants c.[53 A > G];[769G > A] p.(Asn18Ser);(Glu257Lys). The detailed variant analysis, in combination with the observation of an associated macular atrophy phenotype, indicated that these variants were disease-causing. This report demonstrates that the variants in NMNAT1 may cause CD or CRD associated with macular atrophy. Genetic investigations of the patients with CD or CRD should include NMNAT1 in the genes examined.

  10. Bayesian detection of causal rare variants under posterior consistency.

    KAUST Repository

    Liang, Faming

    2013-07-26

    Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD), to tackle this problem. The new method simultaneously addresses two issues: (i) (Global association test) Are there any of the variants associated with the disease, and (ii) (Causal variant detection) Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI) Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.

  11. Bayesian detection of causal rare variants under posterior consistency.

    Directory of Open Access Journals (Sweden)

    Faming Liang

    Full Text Available Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD, to tackle this problem. The new method simultaneously addresses two issues: (i (Global association test Are there any of the variants associated with the disease, and (ii (Causal variant detection Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.

  12. Bayesian detection of causal rare variants under posterior consistency.

    KAUST Repository

    Liang, Faming; Xiong, Momiao

    2013-01-01

    Identification of causal rare variants that are associated with complex traits poses a central challenge on genome-wide association studies. However, most current research focuses only on testing the global association whether the rare variants in a given genomic region are collectively associated with the trait. Although some recent work, e.g., the Bayesian risk index method, have tried to address this problem, it is unclear whether the causal rare variants can be consistently identified by them in the small-n-large-P situation. We develop a new Bayesian method, the so-called Bayesian Rare Variant Detector (BRVD), to tackle this problem. The new method simultaneously addresses two issues: (i) (Global association test) Are there any of the variants associated with the disease, and (ii) (Causal variant detection) Which variants, if any, are driving the association. The BRVD ensures the causal rare variants to be consistently identified in the small-n-large-P situation by imposing some appropriate prior distributions on the model and model specific parameters. The numerical results indicate that the BRVD is more powerful for testing the global association than the existing methods, such as the combined multivariate and collapsing test, weighted sum statistic test, RARECOVER, sequence kernel association test, and Bayesian risk index, and also more powerful for identification of causal rare variants than the Bayesian risk index method. The BRVD has also been successfully applied to the Early-Onset Myocardial Infarction (EOMI) Exome Sequence Data. It identified a few causal rare variants that have been verified in the literature.

  13. Amino acid changes in disease-associated variants differ radically from variants observed in the 1000 genomes project dataset.

    Directory of Open Access Journals (Sweden)

    Tjaart A P de Beer

    Full Text Available The 1000 Genomes Project data provides a natural background dataset for amino acid germline mutations in humans. Since the direction of mutation is known, the amino acid exchange matrix generated from the observed nucleotide variants is asymmetric and the mutabilities of the different amino acids are very different. These differences predominantly reflect preferences for nucleotide mutations in the DNA (especially the high mutation rate of the CpG dinucleotide, which makes arginine mutability very much higher than other amino acids rather than selection imposed by protein structure constraints, although there is evidence for the latter as well. The variants occur predominantly on the surface of proteins (82%, with a slight preference for sites which are more exposed and less well conserved than random. Mutations to functional residues occur about half as often as expected by chance. The disease-associated amino acid variant distributions in OMIM are radically different from those expected on the basis of the 1000 Genomes dataset. The disease-associated variants preferentially occur in more conserved sites, compared to 1000 Genomes mutations. Many of the amino acid exchange profiles appear to exhibit an anti-correlation, with common exchanges in one dataset being rare in the other. Disease-associated variants exhibit more extreme differences in amino acid size and hydrophobicity. More modelling of the mutational processes at the nucleotide level is needed, but these observations should contribute to an improved prediction of the effects of specific variants in humans.

  14. Electrophoretic variants of blood proteins in japanese, 5

    International Nuclear Information System (INIS)

    Fujita, Mikio; Satoh, Chiyoko; Asakawa, Jun-ichi; Nagahata, Yuko; Tanaka, Yoshiko; Hazama, Ryuji; Goriki, Kazuaki.

    1985-08-01

    The plasma ceruloplasmin (CP) of 22,367 children of atomic bomb survivors in Hiroshima and Nagasaki was examined for variants by electrophoresis. The sample was composed of 14,964 unrelated children and 7,403 siblings of the unrelated persons. A total of seven types of electrophoretic variants were detected; four migrating anodally and three cathodally to the normal B band. We have reported two of these variants, CP A sub(NG1) and CP C sub(NG1), previously but the other five, CP A sub(NG2), CP A sub(HR1), CP A sub(HR2), CP C sub(HR1), and CP C sub(HR2), are newly identified. The allelic frequency of CP*CNG1 was 0.00916, so that the variant is considered to be a polymorphic allele. Homozygosity for the CP*CNG1 allele was detected in five individuals. This is the first report of a homozygous phenotype for a CP variant in a Japanese population. Family study of the new five variants all demonstrated patterns of codominant inheritance. (author)

  15. Association analysis identifies ZNF750 regulatory variants in psoriasis

    Directory of Open Access Journals (Sweden)

    Birnbaum Ramon Y

    2011-12-01

    Full Text Available Abstract Background Mutations in the ZNF750 promoter and coding regions have been previously associated with Mendelian forms of psoriasis and psoriasiform dermatitis. ZNF750 encodes a putative zinc finger transcription factor that is highly expressed in keratinocytes and represents a candidate psoriasis gene. Methods We examined whether ZNF750 variants were associated with psoriasis in a large case-control population. We sequenced the promoter and exon regions of ZNF750 in 716 Caucasian psoriasis cases and 397 Caucasian controls. Results We identified a total of 47 variants, including 38 rare variants of which 35 were novel. Association testing identified two ZNF750 haplotypes associated with psoriasis (p ZNF750 promoter and 5' UTR variants displayed a 35-55% reduction of ZNF750 promoter activity, consistent with the promoter activity reduction seen in a Mendelian psoriasis family with a ZNF750 promoter variant. However, the rare promoter and 5' UTR variants identified in this study did not strictly segregate with the psoriasis phenotype within families. Conclusions Two haplotypes of ZNF750 and rare 5' regulatory variants of ZNF750 were found to be associated with psoriasis. These rare 5' regulatory variants, though not causal, might serve as a genetic modifier of psoriasis.

  16. [Clinico-pathogenetic variants of chronic gastritis].

    Science.gov (United States)

    Chernin, V V; Dzhulaĭ, G S

    2004-01-01

    To evaluate specific features of the course of chronic gastritis (CG), morphofunctional condition of gastric mucosa, vegetative regulation, adrenergic and cholinergic shifts, histamine metabolism and effects of exogenic and endogenic risk factors in CG patients; to study clinicopathogenetic variants of CG. A total of 311 CG patients aged from 16 to 72 years were studied. They were divided into three groups by their gastric mucosa condition. The control group consisted of 30 healthy donors. The following parameters were studied: visual and histological condition of gastric mucosa, total acidity, the levels of free hydrochloric acid, pepsin, bioelectric gastric activity, general autonomic tonicity, cholinesterase activity. Three clinicopathogenetic variants of the disease have been identified. Variant 1 was characterized by a recurrent course, subjective manifestation of the disease only in exacerbation, surface (primarily antral) mucosal affection, normal or enhanced secretory and motor functions of the stomach, adequate reaction of acid production to caffeine and histamine stimulation, parasympathicotonia, absolute hyperhistaminemia, relative hypoacetylcholinemia, subnormal urinary excretion of adrenalin. Variant 2 manifested with rare recurrences, longer and more severe exacerbations, frequent spontaneous and provoked aggravations, moderate focal atrophy of the mucosa, secretory insufficiency with adequate reaction to histamine and minor to caffeine stimuli, hypomotor gastric dyskinesia, vegetative eutonia, normohistaminemia, absolute hypoacetylcholinemia, subnormal urinary excretion of noradrenaline. Variant 3 runs without definite remissions and exacerbations, with continuous abdominal pain and dyspepsia, frequent spontaneous aggravations, marked extended mucosal atrophy with secretory insufficiency up to achlorhydria, no stimulation of acid production in response to caffeine and histamine, gastric hypomotility, sympathicotonia, absolute hypohistaminemia

  17. Analysis of the energy development variants

    International Nuclear Information System (INIS)

    Tsvetanov, P.

    1990-01-01

    Analysis of the variants of energy development is made as the third stage of a procedure of energy-economy interrelations dynamics study, the other two stages being the scenarios description and the formulation of the variants. This stage includes a research on the dimensions and the dynamics of the resources demands, the general features and the trends of the national energy development. There is a presentation of a comparative analysis of the variants in terms of economic indices and energy values, computed by the model IMPACT-B. A resource evaluation of the development variants is given in terms of investments, requirements (direct, indirect and total) and limited national resources demands of the energy system. The trends of the national energy development discussed are: trends characterizing the changes in the structure of the energy consumption, resulting from changes in the economy; trends of the energy system impact on the productivity of labor; general trends of the proportionality in the industrial, the household and services sector development. 16 refs., 16 figs., 4 tabs. (R.Ts.)

  18. Detecting very low allele fraction variants using targeted DNA sequencing and a novel molecular barcode-aware variant caller.

    Science.gov (United States)

    Xu, Chang; Nezami Ranjbar, Mohammad R; Wu, Zhong; DiCarlo, John; Wang, Yexun

    2017-01-03

    Detection of DNA mutations at very low allele fractions with high accuracy will significantly improve the effectiveness of precision medicine for cancer patients. To achieve this goal through next generation sequencing, researchers need a detection method that 1) captures rare mutation-containing DNA fragments efficiently in the mix of abundant wild-type DNA; 2) sequences the DNA library extensively to deep coverage; and 3) distinguishes low level true variants from amplification and sequencing errors with high accuracy. Targeted enrichment using PCR primers provides researchers with a convenient way to achieve deep sequencing for a small, yet most relevant region using benchtop sequencers. Molecular barcoding (or indexing) provides a unique solution for reducing sequencing artifacts analytically. Although different molecular barcoding schemes have been reported in recent literature, most variant calling has been done on limited targets, using simple custom scripts. The analytical performance of barcode-aware variant calling can be significantly improved by incorporating advanced statistical models. We present here a highly efficient, simple and scalable enrichment protocol that integrates molecular barcodes in multiplex PCR amplification. In addition, we developed smCounter, an open source, generic, barcode-aware variant caller based on a Bayesian probabilistic model. smCounter was optimized and benchmarked on two independent read sets with SNVs and indels at 5 and 1% allele fractions. Variants were called with very good sensitivity and specificity within coding regions. We demonstrated that we can accurately detect somatic mutations with allele fractions as low as 1% in coding regions using our enrichment protocol and variant caller.

  19. The phosducin-like protein PhLP1 impacts regulation of glycoside hydrolases and light response in Trichoderma reesei

    Directory of Open Access Journals (Sweden)

    Tisch Doris

    2011-12-01

    Full Text Available Abstract Background In the biotechnological workhorse Trichoderma reesei (Hypocrea jecorina transcription of cellulase genes as well as efficiency of the secreted cellulase mixture are modulated by light. Components of the heterotrimeric G-protein pathway interact with light-dependent signals, rendering this pathway a key regulator of cellulase gene expression. Results As regulators of heterotrimeric G-protein signaling, class I phosducin-like proteins, are assumed to act as co-chaperones for G-protein beta-gamma folding and exert their function in response to light in higher eukaryotes. Our results revealed light responsive transcription of the T. reesei class I phosducin-like protein gene phlp1 and indicate a light dependent function of PhLP1 also in fungi. We showed the functions of PhLP1, GNB1 and GNG1 in the same pathway, with one major output being the regulation of transcription of glycoside hydrolase genes including cellulase genes in T. reesei. We found no direct correlation between the growth rate and global regulation of glycoside hydrolases, which suggests that regulation of growth does not occur only at the level of substrate degradation efficiency. Additionally, PhLP1, GNB1 and GNG1 are all important for proper regulation of light responsiveness during long term exposure. In their absence, the amount of light regulated genes increased from 2.7% in wild type to 14% in Δphlp1. Besides from the regulation of degradative enzymes, PhLP1 was also found to impact on the transcription of genes involved in sexual development, which was in accordance with decreased efficiency of fruiting body formation in Δphlp1. The lack of GNB1 drastically diminished ascospore discharge in T. reesei. Conclusions The heterotrimeric G-protein pathway is crucial for the interconnection of nutrient signaling and light response of T. reesei, with the class I phosducin-like protein PhLP1, GNB1 and GNG1 acting as important nodes, which influence light

  20. Ras GTPases Modulate Morphogenesis, Sporulation and Cellulase Gene Expression in the Cellulolytic Fungus Trichoderma reesei

    Science.gov (United States)

    Zhang, Jiwei; Zhang, Yanmei; Zhong, Yaohua; Qu, Yinbo; Wang, Tianhong

    2012-01-01

    Background The model cellulolytic fungus Trichoderma reesei (teleomorph Hypocrea jecorina) is capable of responding to environmental cues to compete for nutrients in its natural saprophytic habitat despite its genome encodes fewer degradative enzymes. Efficient signalling pathways in perception and interpretation of environmental signals are indispensable in this process. Ras GTPases represent a kind of critical signal proteins involved in signal transduction and regulation of gene expression. In T. reesei the genome contains two Ras subfamily small GTPases TrRas1 and TrRas2 homologous to Ras1 and Ras2 from S. cerevisiae, but their functions remain unknown. Methodology/Principal Findings Here, we have investigated the roles of GTPases TrRas1 and TrRas2 during fungal morphogenesis and cellulase gene expression. We show that both TrRas1 and TrRas2 play important roles in some cellular processes such as polarized apical growth, hyphal branch formation, sporulation and cAMP level adjustment, while TrRas1 is more dominant in these processes. Strikingly, we find that TrRas2 is involved in modulation of cellulase gene expression. Deletion of TrRas2 results in considerably decreased transcription of cellulolytic genes upon growth on cellulose. Although the strain carrying a constitutively activated TrRas2G16V allele exhibits increased cellulase gene transcription, the cbh1 and cbh2 expression in this mutant still strictly depends on cellulose, indicating TrRas2 does not directly mediate the transmission of the cellulose signal. In addition, our data suggest that the effect of TrRas2 on cellulase gene is exerted through regulation of transcript abundance of cellulase transcription factors such as Xyr1, but the influence is independent of cAMP signalling pathway. Conclusions/Significance Together, these findings elucidate the functions for Ras signalling of T. reesei in cellular morphogenesis, especially in cellulase gene expression, which contribute to deciphering the

  1. Identifying structural variants using linked-read sequencing data.

    Science.gov (United States)

    Elyanow, Rebecca; Wu, Hsin-Ta; Raphael, Benjamin J

    2017-11-03

    Structural variation, including large deletions, duplications, inversions, translocations, and other rearrangements, is common in human and cancer genomes. A number of methods have been developed to identify structural variants from Illumina short-read sequencing data. However, reliable identification of structural variants remains challenging because many variants have breakpoints in repetitive regions of the genome and thus are difficult to identify with short reads. The recently developed linked-read sequencing technology from 10X Genomics combines a novel barcoding strategy with Illumina sequencing. This technology labels all reads that originate from a small number (~5-10) DNA molecules ~50Kbp in length with the same molecular barcode. These barcoded reads contain long-range sequence information that is advantageous for identification of structural variants. We present Novel Adjacency Identification with Barcoded Reads (NAIBR), an algorithm to identify structural variants in linked-read sequencing data. NAIBR predicts novel adjacencies in a individual genome resulting from structural variants using a probabilistic model that combines multiple signals in barcoded reads. We show that NAIBR outperforms several existing methods for structural variant identification - including two recent methods that also analyze linked-reads - on simulated sequencing data and 10X whole-genome sequencing data from the NA12878 human genome and the HCC1954 breast cancer cell line. Several of the novel somatic structural variants identified in HCC1954 overlap known cancer genes. Software is available at compbio.cs.brown.edu/software. braphael@princeton.edu. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  2. Persistent trigeminal artery/persistent trigeminal artery variant and coexisting variants of the head and neck vessels diagnosed using 3 T MRA

    International Nuclear Information System (INIS)

    Bai, M.; Guo, Q.; Li, S.

    2013-01-01

    Aim: To report the prevalence and characteristic features of persistent trigeminal artery (PTA), PTA variant (PTAV), and other variants of the head and neck vessels, identified using magnetic resonance angiography (MRA). Materials and methods: The three-dimensional (3D) time of flight (TOF) MRA and 3D contrast-enhanced (CE) MRA images of 6095 consecutive patients who underwent 3 T MRA at Liaocheng People's Hospital from 1 September 2008 through 31 May 2012 were retrospectively reviewed and analysed. Thirty-two patients were excluded because of suboptimal image quality or internal carotid artery (ICA) occlusion. Results: The prevalence of both PTA and PTAV was 0.63% (PTA, 26 cases; PTAV, 12 cases). The prevalence of coexisting variants of the head and neck vessels in cases of PTA/PTAV was 52.6% (20 of 38 cases). The vascular variants that coexisted with cases of PTA/PTAV were as follows: the intracranial arteries varied in 10 cases, the origin of the supra-aortic arteries varied in nine cases, the vertebral artery (VA) varied in 14 cases, and six cases displayed fenestrations. Fifteen of the 20 cases contained more than two types of variants. Conclusion: The prevalence of both PTA and PTAV was 0.63%. Although PTA and PTAV are rare vascular variants, they frequently coexist with other variants of the head and neck vessels. Multiple vascular variations can coexist in a single patient. Recognizing PTA, PTAV, and other variants of the head and neck vessels is crucial when planning a neuroradiological intervention or surgery. Recognizing the medial PTA is very important in clinical practice when performing trans-sphenoidal surgery on the pituitary as failure to do so could result in massive haemorrhage

  3. Developing consistent pronunciation models for phonemic variants

    CSIR Research Space (South Africa)

    Davel, M

    2006-09-01

    Full Text Available Pronunciation lexicons often contain pronunciation variants. This can create two problems: It can be difficult to define these variants in an internally consistent way and it can also be difficult to extract generalised grapheme-to-phoneme rule sets...

  4. Comparison of the BioRad Variant and Primus Ultra2 high-pressure liquid chromatography (HPLC) instruments for the detection of variant hemoglobins.

    Science.gov (United States)

    Gosselin, R C; Carlin, A C; Dwyre, D M

    2011-04-01

    Hemoglobin variants are a result of genetic changes resulting in abnormal or dys-synchronous hemoglobin chain production (thalassemia) or the generation of hemoglobin chain variants such as hemoglobin S. Automated high-pressure liquid chromatography (HPLC) systems have become the method of choice for the evaluation of patients suspected with hemoglobinopathies. In this study, we evaluated the performance of two HPLC methods used in the detection of common hemoglobin variants: Variant and Ultra2. There were 377 samples tested, 26% (99/377) with HbS, 8.5% (32/377) with HbC, 20.7% (78/377) with other hemoglobin variant or thalassemia, and 2.9% with increased hemoglobin A(1) c. The interpretations of each chromatograph were compared. There were no differences noted for hemoglobins A(0), S, or C. There were significant differences between HPLC methods for hemoglobins F, A(2), and A(1) c. However, there was good concordance between normal and abnormal interpretations (97.9% and 96.2%, respectively). Both Variant and Ultra2 HPLC methods were able to detect most common hemoglobin variants. There was better discrimination for fast hemoglobins, between hemoglobins E and A(2), and between hemoglobins S and F using the Ultra2 HPLC method. © 2010 Blackwell Publishing Ltd.

  5. Variants of PLCXD3 are not associated with variant or sporadic Creutzfeldt-Jakob disease in a large international study.

    Science.gov (United States)

    Balendra, Rubika; Uphill, James; Collinson, Claire; Druyeh, Ronald; Adamson, Gary; Hummerich, Holger; Zerr, Inga; Gambetti, Pierluigi; Collinge, John; Mead, Simon

    2016-04-07

    Human prion diseases are relentlessly progressive neurodegenerative disorders which include sporadic Creutzfeldt-Jakob disease (sCJD) and variant CJD (vCJD). Aside from variants of the prion protein gene (PRNP) replicated association at genome-wide levels of significance has proven elusive. A recent association study identified variants in or near to the PLCXD3 gene locus as strong disease risk factors in multiple human prion diseases. This study claimed the first non-PRNP locus to be highly significantly associated with prion disease in genomic studies. A sub-study of a genome-wide association study with imputation aiming to replicate the finding at PLCXD3 including 129 vCJD and 2500 sCJD samples. Whole exome sequencing to identify rare coding variants of PLCXD3. Imputation of relevant polymorphisms was accurate based on wet genotyping of a sample. We found no supportive evidence that PLCXD3 variants are associated with disease. The marked discordance in vCJD genotype frequencies between studies, despite extensive overlap in vCJD cases, and the finding of Hardy-Weinberg disequilibrium in the original study, suggests possible reasons for the discrepancies between studies.

  6. A genetic electrophoretic variant of high-sulfur hair proteins for forensic hair comparisons. I. Characterization of variant high-sulfur proteins of human hair.

    Science.gov (United States)

    Miyake, B

    1989-02-01

    In a survey of the proteins from human hair, a genetic electrophoretic variant has been observed in the high-sulfur protein region. S-carboxymethylated proteins were examined by 15% polyacrylamide gel electrophoresis at pH 8.9. Out of 150 unrelated samples of Japanese head hairs analyzed, 107 showed 6 major high-sulfur protein bands (normal) and the remaining 43 samples showed an additional high-sulfur protein band (variant). Of 21 Caucasian samples analyzed only one variant sample was found. Characterization of the proteins by two-dimensional electrophoresis evidenced a variant protein spot which showed an apparent molecular weight of 30 k Da. Isoelectric points of the high-sulfur proteins ranged from 3.25-3.55 and that of variant protein band from 3.3-3.4. Family studies of 21 matings resulting in 49 children indicated that this variant was inherited in an autosomal fashion.

  7. ABCA7 rare variants and Alzheimer disease risk.

    Science.gov (United States)

    Le Guennec, Kilan; Nicolas, Gaël; Quenez, Olivier; Charbonnier, Camille; Wallon, David; Bellenguez, Céline; Grenier-Boley, Benjamin; Rousseau, Stéphane; Richard, Anne-Claire; Rovelet-Lecrux, Anne; Bacq, Delphine; Garnier, Jean-Guillaume; Olaso, Robert; Boland, Anne; Meyer, Vincent; Deleuze, Jean-François; Amouyel, Philippe; Munter, Hans Markus; Bourque, Guillaume; Lathrop, Mark; Frebourg, Thierry; Redon, Richard; Letenneur, Luc; Dartigues, Jean-François; Pasquier, Florence; Rollin-Sillaire, Adeline; Génin, Emmanuelle; Lambert, Jean-Charles; Hannequin, Didier; Campion, Dominique

    2016-06-07

    To study the association between ABCA7 rare coding variants and Alzheimer disease (AD) in a case-control setting. We conducted a whole exome analysis among 484 French patients with early-onset AD and 590 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of ABCA7 loss of function (LOF) and predicted damaging missense variants in cases (odds ratio [OR] 3.40, 95% confidence interval [CI] 1.68-7.35, p = 0.0002). Performing a meta-analysis with previously published data, we found that in a combined sample of 1,256 patients and 1,347 controls from France and Belgium, the OR was 2.81 (95% CI 1.89-4.20, p = 3.60 × 10(-7)). These results confirm that ABCA7 LOF variants are enriched in patients with AD and extend this finding to predicted damaging missense variants. © 2016 American Academy of Neurology.

  8. Electrophoretic variants of blood proteins in Japanese, 7

    International Nuclear Information System (INIS)

    Satoh, Chiyoko; Takahashi, Norio; Kimura, Yasukazu; Miura, Akiko; Kaneko, Junko; Fujita, Mikio; Toyama, Kyoko.

    1986-11-01

    A total of 16,835 children, of whom 11,737 are unrelated, from Hiroshima and Nagasaki were examined for erythrocyte cytoplasmic glutamate-oxaloacetate transaminase (GOT1) by starch gel electrophoresis. A variant allele named GOT1*2HR1 which seems to be identical with GOT1*2 was encountered in polymorphic frequency. Five kinds of rare variants, 3NG1, 4NG1, 5NG1, 6HR1, and 7NG1 were encountered in a total of 109 children. Except for 7NG1 for which complete family study was unable, family studies confirmed the genetic nature of these rare variants, since for all instances in which both parents could be examined, one of the parents exhibited the same variant as that of their child. Thermostability profiles of these six variants were normal. The enzyme activities of five were decreased, while the value of one was normal compared to that of GOT1 1. (author)

  9. Identifying noncoding risk variants using disease-relevant gene regulatory networks.

    Science.gov (United States)

    Gao, Long; Uzun, Yasin; Gao, Peng; He, Bing; Ma, Xiaoke; Wang, Jiahui; Han, Shizhong; Tan, Kai

    2018-02-16

    Identifying noncoding risk variants remains a challenging task. Because noncoding variants exert their effects in the context of a gene regulatory network (GRN), we hypothesize that explicit use of disease-relevant GRNs can significantly improve the inference accuracy of noncoding risk variants. We describe Annotation of Regulatory Variants using Integrated Networks (ARVIN), a general computational framework for predicting causal noncoding variants. It employs a set of novel regulatory network-based features, combined with sequence-based features to infer noncoding risk variants. Using known causal variants in gene promoters and enhancers in a number of diseases, we show ARVIN outperforms state-of-the-art methods that use sequence-based features alone. Additional experimental validation using reporter assay further demonstrates the accuracy of ARVIN. Application of ARVIN to seven autoimmune diseases provides a holistic view of the gene subnetwork perturbed by the combinatorial action of the entire set of risk noncoding mutations.

  10. COMPARISON OF THE TEST VARIANTS IN ENTRANCE EXAMINATIONS

    Directory of Open Access Journals (Sweden)

    KLŮFA, Jindřich

    2016-12-01

    Full Text Available The paper contains an analysis of the differences of number of points in the test in mathematics between test variants, which were used in the entrance examinations at the Faculty of Business Administration at University of Economics in Prague in 2015. The differences may arise due to the varying difficulty of variants for students, but also because of the different level of knowledge of students who write these variants. This problem we shall study in present paper. The aim of this paper is to study dependence of the results of entrance examinations in mathematics on test variants. The results obtained will be used for further improvement of the admission process at University of Economics.

  11. Superior and inferior vena cavae: Embryology, variants, and pathology

    International Nuclear Information System (INIS)

    Mendelson, D.S.; Mitty, H.; Janus, C.; Gendal, E.; Berson, B.

    1987-01-01

    The superior and inferior venae cavae may be involved in a host of disease processes. Knowledge of the normal anatomy and variants of these structures is valuable in interpreting plain films and the results of angiographic procedures and all cross-sectional modalities. The authors review the embryology of venae cavae and proceed to describe their normal anatomy and variants. An awareness of the variants can prevent mistaking variants for pathologic processes. Finally, the authors describe pathology involving these vessels and demonstrate the radiographic manifestations

  12. Golden Rule of Morphology and Variants of Word forms

    Directory of Open Access Journals (Sweden)

    Hlaváčová Jaroslava

    2017-12-01

    Full Text Available In many languages, some words can be written in several ways. We call them variants. Values of all their morphological categories are identical, which leads to an identical morphological tag. Together with the identical lemma, we have two or more wordforms with the same morphological description. This ambiguity may cause problems in various NLP applications. There are two types of variants – those affecting the whole paradigm (global variants and those affecting only wordforms sharing some combinations of morphological values (inflectional variants. In the paper, we propose means how to tag all wordforms, including their variants, unambiguously. We call this requirement “Golden rule of morphology”. The paper deals mainly with Czech, but the ideas can be applied to other languages as well.

  13. N-terminal nesprin-2 variants regulate β-catenin signalling

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Qiuping; Minaisah, Rose-Marie; Ferraro, Elisa; Li, Chen; Porter, Lauren J.; Zhou, Can; Gao, Fang; Zhang, Junyi; Rajgor, Dipen; Autore, Flavia; Shanahan, Catherine M.; Warren, Derek T., E-mail: derek.warren@kcl.ac.uk

    2016-07-15

    The spatial compartmentalisation of biochemical signalling pathways is essential for cell function. Nesprins are a multi-isomeric family of proteins that have emerged as signalling scaffolds, herein, we investigate the localisation and function of novel nesprin-2 N-terminal variants. We show that these nesprin-2 variants display cell specific distribution and reside in both the cytoplasm and nucleus. Immunofluorescence microscopy revealed that nesprin-2 N-terminal variants colocalised with β-catenin at cell-cell junctions in U2OS cells. Calcium switch assays demonstrated that nesprin-2 and β-catenin are lost from cell-cell junctions in low calcium conditions whereas emerin localisation at the NE remained unaltered, furthermore, an N-terminal fragment of nesprin-2 was sufficient for cell-cell junction localisation and interacted with β-catenin. Disruption of these N-terminal nesprin-2 variants, using siRNA depletion resulted in loss of β-catenin from cell-cell junctions, nuclear accumulation of active β-catenin and augmented β-catenin transcriptional activity. Importantly, we show that U2OS cells lack nesprin-2 giant, suggesting that the N-terminal nesprin-2 variants regulate β-catenin signalling independently of the NE. Together, these data identify N-terminal nesprin-2 variants as novel regulators of β-catenin signalling that tether β-catenin to cell-cell contacts to inhibit β-catenin transcriptional activity. - Highlights: • N-terminal nesprin-2 variants display cell specific expression patterns. • N-terminal spectrin repeats of nesprin-2 interact with β-catenin. • N-terminal nesprin-2 variants scaffold β-catenin at cell-cell junctions.. • Nesprin-2 variants play multiple roles in β-catenin signalling.

  14. Fundamental Characteristics of Industrial Variant Specification Systems

    DEFF Research Database (Denmark)

    Hansen, Benjamin Loer; Hvam, Lars

    2004-01-01

    fundamental concepts related to this task, which are relevant to understand for academia and practitioners working with the subject. This is done through a description of variant specification tasks and typical aspects of system solutions. To support the description of variant specification tasks and systems...

  15. Microsatellite Instability Use in Mismatch Repair Gene Sequence Variant Classification

    Directory of Open Access Journals (Sweden)

    Bryony A. Thompson

    2015-03-01

    Full Text Available Inherited mutations in the DNA mismatch repair genes (MMR can cause MMR deficiency and increased susceptibility to colorectal and endometrial cancer. Microsatellite instability (MSI is the defining molecular signature of MMR deficiency. The clinical classification of identified MMR gene sequence variants has a direct impact on the management of patients and their families. For a significant proportion of cases sequence variants of uncertain clinical significance (also known as unclassified variants are identified, constituting a challenge for genetic counselling and clinical management of families. The effect on protein function of these variants is difficult to interpret. The presence or absence of MSI in tumours can aid in determining the pathogenicity of associated unclassified MMR gene variants. However, there are some considerations that need to be taken into account when using MSI for variant interpretation. The use of MSI and other tumour characteristics in MMR gene sequence variant classification will be explored in this review.

  16. HFE gene variants affect iron in the brain.

    Science.gov (United States)

    Nandar, Wint; Connor, James R

    2011-04-01

    Iron accumulation in the brain and increased oxidative stress are consistent observations in many neurodegenerative diseases. Thus, we have begun examination into gene mutations or allelic variants that could be associated with loss of iron homeostasis. One of the mechanisms leading to iron overload is a mutation in the HFE gene, which is involved in iron metabolism. The 2 most common HFE gene variants are C282Y (1.9%) and H63D (8.9%). The C282Y HFE variant is more commonly associated with hereditary hemochromatosis, which is an autosomal recessive disorder, characterized by iron overload in a number of systemic organs. The H63D HFE variant appears less frequently associated with hemochromatosis, but its role in the neurodegenerative diseases has received more attention. At the cellular level, the HFE mutant protein resulting from the H63D HFE gene variant is associated with iron dyshomeostasis, increased oxidative stress, glutamate release, tau phosphorylation, and alteration in inflammatory response, each of which is under investigation as a contributing factor to neurodegenerative diseases. Therefore, the HFE gene variants are proposed to be genetic modifiers or a risk factor for neurodegenerative diseases by establishing an enabling milieu for pathogenic agents. This review will discuss the current knowledge of the association of the HFE gene variants with neurodegenerative diseases: amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and ischemic stroke. Importantly, the data herein also begin to dispel the long-held view that the brain is protected from iron accumulation associated with the HFE mutations.

  17. Differential Expression Profile of ZFX Variants Discriminates Breast Cancer Subtypes

    Science.gov (United States)

    Pourkeramati, Fatemeh; Asadi, Malek Hossein; Shakeri, Shahryar; Farsinejad, Alireza

    2018-05-13

    ZFX is a transcriptional regulator in embryonic stem cells that plays an important role in pluripotency and self-renewal. ZFX is widely expressed in pluripotent stem cells and is down-regulated during differentiation of embryonic stem cells. ZFX has five different variants that encode three different protein isoforms. While several reports have determined the overexpression of ZFX in a variety of somatic cancers, the expression of ZFX-spliced variants in cancer cells is not well-understood. We investigated the expression of ZFX variants in a series of breast cancer tissues and cell lines using quantitative PCR. The expression of ZFX variant 1/3 was higher in tumor tissue compared to marginal tissue. In contrast, the ZFX variant 5 was down-regulated in tumor tissues. While the ZFX variant 1/3 and ZFX variant 5 expression significantly increased in low-grade tumors, ZFX variant 4 was strongly expressed in high-grade tumors and demonstrating lymphatic invasion. In addition, our result revealed a significant association between the HER2 status and the expression of ZFX-spliced variants. Our data suggest that the expression of ZFX-spliced transcripts varies between different types of breast cancer and may contribute to their tumorigenesis process. Hence, ZFX-spliced transcripts could be considered as novel tumor markers with a probable value in diagnosis, prognosis, and therapy of breast cancer.

  18. Genotype–phenotype correlations in individuals with pathogenic RERE variants

    Science.gov (United States)

    Jordan, Valerie K.; Fregeau, Brieana; Ge, Xiaoyan; Giordano, Jessica; Wapner, Ronald J.; Balci, Tugce B.; Carter, Melissa T.; Bernat, John A.; Moccia, Amanda N.; Srivastava, Anshika; Martin, Donna M.; Bielas, Stephanie L.; Pappas, John; Svoboda, Melissa D.; Rio, Marlène; Boddaert, Nathalie; Cantagrel, Vincent; Lewis, Andrea M.; Scaglia, Fernando; Kohler, Jennefer N.; Bernstein, Jonathan A.; Dries, Annika M.; Rosenfeld, Jill A.; DeFilippo, Colette; Thorson, Willa; Yang, Yaping; Sherr, Elliott H.; Bi, Weimin; Scott, Daryl A.

    2018-01-01

    Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7. PMID:29330883

  19. Poisson Approximation-Based Score Test for Detecting Association of Rare Variants.

    Science.gov (United States)

    Fang, Hongyan; Zhang, Hong; Yang, Yaning

    2016-07-01

    Genome-wide association study (GWAS) has achieved great success in identifying genetic variants, but the nature of GWAS has determined its inherent limitations. Under the common disease rare variants (CDRV) hypothesis, the traditional association analysis methods commonly used in GWAS for common variants do not have enough power for detecting rare variants with a limited sample size. As a solution to this problem, pooling rare variants by their functions provides an efficient way for identifying susceptible genes. Rare variant typically have low frequencies of minor alleles, and the distribution of the total number of minor alleles of the rare variants can be approximated by a Poisson distribution. Based on this fact, we propose a new test method, the Poisson Approximation-based Score Test (PAST), for association analysis of rare variants. Two testing methods, namely, ePAST and mPAST, are proposed based on different strategies of pooling rare variants. Simulation results and application to the CRESCENDO cohort data show that our methods are more powerful than the existing methods. © 2016 John Wiley & Sons Ltd/University College London.

  20. Cellulase variants with improved expression, activity and stability, and use thereof

    Science.gov (United States)

    Aehle, Wolfgang; Bott, Richard R; Bower, Benjamin; Caspi, Jonathan; Estell, David A; Goedegebuur, Frits; Hommes, Ronaldus W.J.; Kaper, Thijs; Kelemen, Bradley; Kralj, Slavko; Van Lieshout, Johan; Nikolaev, Igor; Van Stigt Thans, Sander; Wallace, Louise; Vogtentanz, Gudrun; Sandgren, Mats

    2014-03-25

    The present disclosure relates to cellulase variants. In particular the present disclosure relates to cellulase variants having improved expression, activity and/or stability. Also described are nucleic acids encoding the cellulase variants, compositions comprising the cellulase variants, and methods of use thereof.

  1. Cellulase variants with improved expression, activity and stability, and use thereof

    Energy Technology Data Exchange (ETDEWEB)

    Aehle, Wolfgang; Bott, Richard R.; Bower, Benjamin S.; Caspi, Jonathan; Goedegebuur, Frits; Hommes, Ronaldus Wilhelmus Joannes; Kaper, Thijs; Kelemen, Bradley R.; Kralj, Slavko; Van Lieshout, Johannes Franciscus Thomas; Nikolaev, Igor; Wallace, Louise; Van Stigt Thans, Sander; Vogtentanz, Gudrun; Sandgren, Mats

    2016-12-20

    The present disclosure relates to cellulase variants. In particular the present disclosure relates to cellulase variants having improved expression, activity and/or stability. Also described are nucleic acids encoding the cellulase variants, compositions comprising the cellulase variants, and methods of use thereof.

  2. Genetic variants of ghrelin in metabolic disorders.

    Science.gov (United States)

    Ukkola, Olavi

    2011-11-01

    An increasing understanding of the role of genes in the development of obesity may reveal genetic variants that, in combination with conventional risk factors, may help to predict an individual's risk for developing metabolic disorders. Accumulating evidence indicates that ghrelin plays a role in regulating food intake and energy homeostasis and it is a reasonable candidate gene for obesity-related co-morbidities. In cross-sectional studies low total ghrelin concentrations and some genetic polymorphisms of ghrelin have been associated with obesity-associated diseases. The present review highlights many of the important problems in association studies of genetic variants and complex diseases. It is known that population-specific differences in reported associations exist. We therefore conclude that more studies on variants of ghrelin gene are needed to perform in different populations to get deeper understanding on the relationship of ghrelin gene and its variants to obesity. Copyright © 2011 Elsevier Inc. All rights reserved.

  3. Isolation of a variant of Candida albicans.

    Science.gov (United States)

    Buckley, H R; Price, M R; Daneo-Moore, L

    1982-01-01

    During the course of Candida albicans antigen production, a variant of this organism was encountered which did not produce hyphae at 37 degrees C. Presented here are some of the characteristics of this variant. It produces hyphae at 25 degrees C on cornmeal agar and synthetic medium plus N-acetylglucosamine and Tween 80. At 37 degrees C, it does not produce hyphae on these media, although C. albicans normally does produce hyphae under these circumstances. In liquid synthetic medium, this variant does not produce hyphae at 37 degrees C. The variant strain was analyzed for DNA, RNA, protein content, and particle size. After 50 to 70 h in balanced exponential-phase growth, particle size distribution was narrow, and there were no differences in the DNA, RNA, or protein content per particle in the two strains. When balanced exponential-phase cultures were brought into stationary phase, both strains contained the same amount of DNA per cell. Images PMID:6752021

  4. Isolation of a variant of Candida albicans.

    Science.gov (United States)

    Buckley, H R; Price, M R; Daneo-Moore, L

    1982-09-01

    During the course of Candida albicans antigen production, a variant of this organism was encountered which did not produce hyphae at 37 degrees C. Presented here are some of the characteristics of this variant. It produces hyphae at 25 degrees C on cornmeal agar and synthetic medium plus N-acetylglucosamine and Tween 80. At 37 degrees C, it does not produce hyphae on these media, although C. albicans normally does produce hyphae under these circumstances. In liquid synthetic medium, this variant does not produce hyphae at 37 degrees C. The variant strain was analyzed for DNA, RNA, protein content, and particle size. After 50 to 70 h in balanced exponential-phase growth, particle size distribution was narrow, and there were no differences in the DNA, RNA, or protein content per particle in the two strains. When balanced exponential-phase cultures were brought into stationary phase, both strains contained the same amount of DNA per cell.

  5. Dataset of mitochondrial genome variants in oncocytic tumors

    Directory of Open Access Journals (Sweden)

    Lihua Lyu

    2018-04-01

    Full Text Available This dataset presents the mitochondrial genome variants associated with oncocytic tumors. These data were obtained by Sanger sequencing of the whole mitochondrial genomes of oncocytic tumors and the adjacent normal tissues from 32 patients. The mtDNA variants are identified after compared with the revised Cambridge sequence, excluding those defining haplogroups of our patients. The pathogenic prediction for the novel missense variants found in this study was performed with the Mitimpact 2 program.

  6. Biochemical characteristics of glucose-6-phosphate dehydrogenase variants among the Malays of Singapore with report of a new non-deficient (GdSingapore) and three deficient variants.

    Science.gov (United States)

    Saha, N; Hong, S H; Wong, H A; Jeyaseelan, K; Tay, J S

    1991-12-01

    Biochemical characteristics of one non-deficient fast G6PD variant (GdSingapore) and six different deficient variants (three new, two Mahidol, one each of Indonesian and Mediterranean) were studied among the Malays of Singapore. The GdSingapore variant had normal enzyme activity (82%) and fast electrophoretic mobilities (140% in TEB buffer, 160% in phosphate and 140% in Tris-HCl buffer systems respectively). This variant is further characterized by normal Km for G6P; utilization of analogues (Gal6P, 2dG6P; dAmNADP), heat stability and pH optimum. The other six deficient G6PD variants had normal electrophoretic mobility in TEB buffer with enzyme activities ranging from 1 to 12% of GdB+. The biochemical characteristics identity them to be 2 Mahidol, 1 Indonesian and 1 Mediterranean variants and three new deficient variants.

  7. Characterization of form variants of Xenorhabdus luminescens.

    NARCIS (Netherlands)

    Gerritsen, L.J.M.; Raay, de G.; Smits, P.H.

    1992-01-01

    From Xenorhabdus luminescens XE-87.3 four variants were isolated. One, which produced a red pigment and antibiotics, was luminescent, and could take up dye from culture media, was considered the primary form (XE-red). A pink-pigmented variant (XE-pink) differed from the primary form only in

  8. Identificação de variantes de hemoglobina em doadores de sangue Identification of hemoglobin variants in blood donor

    Directory of Open Access Journals (Sweden)

    Ana C. Bonini-Domingos

    2004-03-01

    Full Text Available Hemoglobinopathies are the most common genetic diseases and affect a great number of individuals in the world, with diverse clinical complications ranging from the almost unnoticeable to lethal consequences. In Brazil the occurrence of hemoglobinopathies is very frequent and influenced by the ethnical groups that are the basis of populations in different regions. The phenotype may be influenced by environmental and genetic factors and by migration. An understanding of these genetic diseases is important for the health and quality of life of the population. In this work we assessed the presence of Hb variants in blood donors from São José do Rio Preto and region, and we observed the occurrence of variants including Hb S and Hb C but in particular the so-called "S-Like" variants. Good determination of the forms of variant hemoglobins is very important to give better guidance to blood donors and their families, and to improve the quality of blood transfusion.

  9. Mouse ribosomal RNA genes contain multiple differentially regulated variants.

    Directory of Open Access Journals (Sweden)

    Hung Tseng

    2008-03-01

    Full Text Available Previous cytogenetic studies suggest that various rDNA chromosomal loci are not equally active in different cell types. Consistent with this variability, rDNA polymorphism is well documented in human and mouse. However, attempts to identify molecularly rDNA variant types, which are regulated individually (i.e., independent of other rDNA variants and tissue-specifically, have not been successful. We report here the molecular cloning and characterization of seven mouse rDNA variants (v-rDNA. The identification of these v-rDNAs was based on restriction fragment length polymorphisms (RFLPs, which are conserved among individuals and mouse strains. The total copy number of the identified variants is less than 100 and the copy number of each individual variant ranges from 4 to 15. Sequence analysis of the cloned v-rDNA identified variant-specific single nucleotide polymorphisms (SNPs in the transcribed region. These SNPs were used to develop a set of variant-specific PCR assays, which permitted analysis of the v-rDNAs' expression profiles in various tissues. These profiles show that three v-rDNAs are expressed in all tissues (constitutively active, two are expressed in some tissues (selectively active, and two are not expressed (silent. These expression profiles were observed in six individuals from three mouse strains, suggesting the pattern is not randomly determined. Thus, the mouse rDNA array likely consists of genetically distinct variants, and some are regulated tissue-specifically. Our results provide the first molecular evidence for cell-type-specific regulation of a subset of rDNA.

  10. Ultrasonographic imaging of papillary thyroid carcinoma variants

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Jung Hee [Dept. of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2017-04-15

    Ultrasonography (US) is routinely used to evaluate thyroid nodules. The US features of papillary thyroid carcinoma (PTC), the most common thyroid malignancy, include hypoechogenicity, spiculated/microlobulated margins, microcalcifications, and a nonparallel orientation. However, many PTC variants have been identified, some of which differ from the classic type of PTC in terms of biological behavior and clinical outcomes. This review describes the US features and clinical implications of the variants of PTC. With the introduction of active surveillance replacing immediate biopsy or surgical treatment of indolent, small PTCs, an understanding of the US characteristics of PTC variants will facilitate the individualized management of patients with PTC.

  11. Treatment of spelling variants in Setswana monolingual dictionaries

    African Journals Online (AJOL)

    user

    . ..... Table 8: Variants of Names of persons and places. Setswana variants. English. Aforika, Aferika. Africa. Baebele, Babele, Beibele. Bible. Ennyelane, Engelane ..... MWEs. As in variation amongst individual words, the MWEs such as idioms.

  12. Human papillomavirus variants among Inuit women in northern Quebec, Canada.

    Science.gov (United States)

    Gauthier, Barbara; Coutlée, Francois; Franco, Eduardo L; Brassard, Paul

    2015-01-01

    Inuit communities in northern Quebec have high rates of human papillomavirus (HPV) infection, cervical cancer and cervical cancer-related mortality as compared to the Canadian population. HPV types can be further classified as intratypic variants based on the extent of homology in their nucleotide sequences. There is limited information on the distribution of intratypic variants in circumpolar areas. Our goal was to describe the HPV intratypic variants and associated baseline characteristics. We collected cervical cell samples in 2002-2006 from 676 Inuit women between the ages of 15 and 69 years in Nunavik. DNA isolates from high-risk HPVs were sequenced to determine the intratypic variant. There were 149 women that were positive for HPVs 16, 18, 31, 33, 35, 45, 52, 56 or 58 during follow-up. There were 5 different HPV16 variants, all of European lineage, among the 57 women positive for this type. There were 8 different variants of HPV18 present and all were of European lineage (n=21). The majority of samples of HPV31 (n=52) were of lineage B. The number of isolates and diversity of the other HPV types was low. Age was the only covariate associated with HPV16 variant category. These frequencies are similar to what was seen in another circumpolar region of Canada, although there appears to be less diversity as only European variants were detected. This study shows that most variants were clustered in one lineage for each HPV type.

  13. Genetic variants influencing phenotypic variance heterogeneity.

    Science.gov (United States)

    Ek, Weronica E; Rask-Andersen, Mathias; Karlsson, Torgny; Enroth, Stefan; Gyllensten, Ulf; Johansson, Åsa

    2018-03-01

    Most genetic studies identify genetic variants associated with disease risk or with the mean value of a quantitative trait. More rarely, genetic variants associated with variance heterogeneity are considered. In this study, we have identified such variance single-nucleotide polymorphisms (vSNPs) and examined if these represent biological gene × gene or gene × environment interactions or statistical artifacts caused by multiple linked genetic variants influencing the same phenotype. We have performed a genome-wide study, to identify vSNPs associated with variance heterogeneity in DNA methylation levels. Genotype data from over 10 million single-nucleotide polymorphisms (SNPs), and DNA methylation levels at over 430 000 CpG sites, were analyzed in 729 individuals. We identified vSNPs for 7195 CpG sites (P mean DNA methylation levels. We further showed that variance heterogeneity between genotypes mainly represents additional, often rare, SNPs in linkage disequilibrium (LD) with the respective vSNP and for some vSNPs, multiple low frequency variants co-segregating with one of the vSNP alleles. Therefore, our results suggest that variance heterogeneity of DNA methylation mainly represents phenotypic effects by multiple SNPs, rather than biological interactions. Such effects may also be important for interpreting variance heterogeneity of more complex clinical phenotypes.

  14. Method of generating ploynucleotides encoding enhanced folding variants

    Energy Technology Data Exchange (ETDEWEB)

    Bradbury, Andrew M.; Kiss, Csaba; Waldo, Geoffrey S.

    2017-05-02

    The invention provides directed evolution methods for improving the folding, solubility and stability (including thermostability) characteristics of polypeptides. In one aspect, the invention provides a method for generating folding and stability-enhanced variants of proteins, including but not limited to fluorescent proteins, chromophoric proteins and enzymes. In another aspect, the invention provides methods for generating thermostable variants of a target protein or polypeptide via an internal destabilization baiting strategy. Internally destabilization a protein of interest is achieved by inserting a heterologous, folding-destabilizing sequence (folding interference domain) within DNA encoding the protein of interest, evolving the protein sequences adjacent to the heterologous insertion to overcome the destabilization (using any number of mutagenesis methods), thereby creating a library of variants. The variants in the library are expressed, and those with enhanced folding characteristics selected.

  15. Influenza A (H3N2) Variant Virus

    Science.gov (United States)

    ... Swine Variant Pandemic Other Influenza A (H3N2) Variant Virus Language: English (US) Español Recommend on Facebook Tweet Share Compartir Influenza viruses that normally circulate in pigs are called “variant” ...

  16. Ankle fracture spur sign is pathognomonic for a variant ankle fracture.

    Science.gov (United States)

    Hinds, Richard M; Garner, Matthew R; Lazaro, Lionel E; Warner, Stephen J; Loftus, Michael L; Birnbaum, Jacqueline F; Burket, Jayme C; Lorich, Dean G

    2015-02-01

    The hyperplantarflexion variant ankle fracture is composed of a posterior tibial lip fracture with posterolateral and posteromedial fracture fragments separated by a vertical fracture line. This infrequently reported injury pattern often includes an associated "spur sign" or double cortical density at the inferomedial tibial metaphysis. The objective of this study was to quantitatively establish the association of the ankle fracture spur sign with the hyperplantarflexion variant ankle fracture. Our clinical database of operative ankle fractures was retrospectively reviewed for the incidence of hyperplantarflexion variant and nonvariant ankle fractures as determined by assessment of injury radiographs, preoperative advanced imaging, and intraoperative observation. Injury radiographs were then evaluated for the presence of the spur sign, and association between the spur sign and variant fractures was analyzed. The incidence of the hyperplantarflexion variant fracture among all ankle fractures was 6.7% (43/640). The spur sign was present in 79% (34/43) of variant fractures and absent in all nonvariant fractures, conferring a specificity of 100% in identifying variant fractures. Positive predictive value and negative predictive value were 100% and 99%, respectively. The ankle fracture spur sign was pathognomonic for the hyperplantarflexion variant ankle fracture. It is important to identify variant fractures preoperatively as patient positioning, operative approach, and fixation construct of variant fractures often differ from those employed for osteosynthesis of nonvariant fractures. Identification of the spur sign should prompt acquisition of advanced imaging to formulate an appropriate operative plan to address the variant fracture pattern. Level III, retrospective comparative study. © The Author(s) 2014.

  17. Holoprosencephaly Variant

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2003-01-01

    Full Text Available The clinical manifestations in 15 patients (6 boys and 9 girls with middle interhemispheric variant (MIH of holoprosencephaly (HPE were compared with classic subtypes (alobar, semilobar, and lobar of HPE in a multicenter study at Stanford University School of Medicine and Lucile Packard Children’s Hospital; Children’s Hospital of Philadelphia; University of California at San Francisco; Texas Scottish Rite Hospital, Dallas; and Kennedy Krieger Institute, Baltimore, MD.

  18. Investigation of the role of TCF4 rare sequence variants in schizophrenia.

    Science.gov (United States)

    Basmanav, F Buket; Forstner, Andreas J; Fier, Heide; Herms, Stefan; Meier, Sandra; Degenhardt, Franziska; Hoffmann, Per; Barth, Sandra; Fricker, Nadine; Strohmaier, Jana; Witt, Stephanie H; Ludwig, Michael; Schmael, Christine; Moebus, Susanne; Maier, Wolfgang; Mössner, Rainald; Rujescu, Dan; Rietschel, Marcella; Lange, Christoph; Nöthen, Markus M; Cichon, Sven

    2015-07-01

    Transcription factor 4 (TCF4) is one of the most robust of all reported schizophrenia risk loci and is supported by several genetic and functional lines of evidence. While numerous studies have implicated common genetic variation at TCF4 in schizophrenia risk, the role of rare, small-sized variants at this locus-such as single nucleotide variants and short indels which are below the resolution of chip-based arrays requires further exploration. The aim of the present study was to investigate the association between rare TCF4 sequence variants and schizophrenia. Exon-targeted resequencing was performed in 190 German schizophrenia patients. Six rare variants at the coding exons and flanking sequences of the TCF4 gene were identified, including two missense variants and one splice site variant. These six variants were then pooled with nine additional rare variants identified in 379 European participants of the 1000 Genomes Project, and all 15 variants were genotyped in an independent German sample (n = 1,808 patients; n = 2,261 controls). These data were then analyzed using six statistical methods developed for the association analysis of rare variants. No significant association (P power analyses suggest that further research into the possible involvement of rare TCF4 sequence variants in schizophrenia risk is warranted by the assessment of larger cohorts with higher statistical power to identify rare variant associations. © 2015 Wiley Periodicals, Inc.

  19. SDS, a structural disruption score for assessment of missense variant deleteriousness

    Directory of Open Access Journals (Sweden)

    Thanawadee ePreeprem

    2014-04-01

    Full Text Available We have developed a novel structure-based evaluation for missense variants that explicitly models protein structure and amino acid properties to predict the likelihood that a variant disrupts protein function. A structural disruption score (SDS is introduced as a measure to depict the likelihood that a case variant is functional. The score is constructed using characteristics that distinguish between causal and neutral variants within a group of proteins. The SDS score is correlated with standard sequence-based deleteriousness, but shows promise for improving discrimination between neutral and causal variants at less conserved sites.The prediction was performed on 3-dimentional structures of 57 gene products whose homozygous SNPs were identified as case-exclusive variants in an exome sequencing study of epilepsy disorders. We contrasted the candidate epilepsy variants with scores for likely benign variants found in the EVS database, and for positive control variants in the same genes that are suspected to promote a range of diseases. To derive a characteristic profile of damaging SNPs, we transformed continuous scores into categorical variables based on the score distribution of each measurement, collected from all possible SNPs in this protein set, where extreme measures were assumed to be deleterious. A second epilepsy dataset was used to replicate the findings. Causal variants tend to receive higher sequence-based deleterious scores, induce larger physico-chemical changes between amino acid pairs, locate in protein domains, buried sites or on conserved protein surface clusters, and cause protein destabilization, relative to negative controls. These measures were agglomerated for each variant. A list of nine high-priority putative functional variants for epilepsy was generated. Our newly developed SDS protocol facilitates SNP prioritization for experimental validation.

  20. Comprehensive genotyping in dyslipidemia: mendelian dyslipidemias caused by rare variants and Mendelian randomization studies using common variants.

    Science.gov (United States)

    Tada, Hayato; Kawashiri, Masa-Aki; Yamagishi, Masakazu

    2017-04-01

    Dyslipidemias, especially hyper-low-density lipoprotein cholesterolemia and hypertriglyceridemia, are important causal risk factors for coronary artery disease. Comprehensive genotyping using the 'next-generation sequencing' technique has facilitated the investigation of Mendelian dyslipidemias, in addition to Mendelian randomization studies using common genetic variants associated with plasma lipids and coronary artery disease. The beneficial effects of low-density lipoprotein cholesterol-lowering therapies on coronary artery disease have been verified by many randomized controlled trials over the years, and subsequent genetic studies have supported these findings. More recently, Mendelian randomization studies have preceded randomized controlled trials. When the on-target/off-target effects of rare variants and common variants exhibit the same direction, novel drugs targeting molecules identified by investigations of rare Mendelian lipid disorders could be promising. Such a strategy could aid in the search for drug discovery seeds other than those for dyslipidemias.

  1. A variational Bayes discrete mixture test for rare variant association.

    Science.gov (United States)

    Logsdon, Benjamin A; Dai, James Y; Auer, Paul L; Johnsen, Jill M; Ganesh, Santhi K; Smith, Nicholas L; Wilson, James G; Tracy, Russell P; Lange, Leslie A; Jiao, Shuo; Rich, Stephen S; Lettre, Guillaume; Carlson, Christopher S; Jackson, Rebecca D; O'Donnell, Christopher J; Wurfel, Mark M; Nickerson, Deborah A; Tang, Hua; Reiner, Alexander P; Kooperberg, Charles

    2014-01-01

    Recently, many statistical methods have been proposed to test for associations between rare genetic variants and complex traits. Most of these methods test for association by aggregating genetic variations within a predefined region, such as a gene. Although there is evidence that "aggregate" tests are more powerful than the single marker test, these tests generally ignore neutral variants and therefore are unable to identify specific variants driving the association with phenotype. We propose a novel aggregate rare-variant test that explicitly models a fraction of variants as neutral, tests associations at the gene-level, and infers the rare-variants driving the association. Simulations show that in the practical scenario where there are many variants within a given region of the genome with only a fraction causal our approach has greater power compared to other popular tests such as the Sequence Kernel Association Test (SKAT), the Weighted Sum Statistic (WSS), and the collapsing method of Morris and Zeggini (MZ). Our algorithm leverages a fast variational Bayes approximate inference methodology to scale to exome-wide analyses, a significant computational advantage over exact inference model selection methodologies. To demonstrate the efficacy of our methodology we test for associations between von Willebrand Factor (VWF) levels and VWF missense rare-variants imputed from the National Heart, Lung, and Blood Institute's Exome Sequencing project into 2,487 African Americans within the VWF gene. Our method suggests that a relatively small fraction (~10%) of the imputed rare missense variants within VWF are strongly associated with lower VWF levels in African Americans.

  2. Glucose 6-phosphate dehydrogenase variants in Japan.

    Science.gov (United States)

    Miwa, S

    1980-01-01

    Fifty-four cases of glucose 6-phosphate dehydrogenase (G6PD) deficiency have so far been reported in Japan. Among them, 21 G6PD variants have been characterized. Nineteen out of the 21 variants were characterized in our laboratory and G6PD Heian and "Kyoto" by others. G6PD Tokyo, Tokushima, Ogikubo, Kurume, Fukushima, Yokohama, Yamaguchi, Wakayama, Akita, Heian and "Kyoto" were classified as Class 1, because all these cases showed chronic hemolytic anemia and severe enzyme deficiency. All these variants showed thermal instability. G6PD Mediterranean-like, Ogori, Gifu and Fukuoka were classified as Class 2, whereas G6PD Hofu, B(-) Chinese, Ube, Konan, Kamiube and Kiwa belonged to Class 3. All the 6 Class 3 variants were found as the results of the screening tests. The incidence of the deficiency in Japanese seems to be 0.1-0.5% but that of the cases which may slow drug-induced hemolysis would be much less. G6PD Ube and Konan appear to be relatively common in Japan.

  3. Dandy-Walker variant in Coffin-Siris syndrome.

    Science.gov (United States)

    Imai, T; Hattori, H; Miyazaki, M; Higuchi, Y; Adachi, S; Nakahata, T

    2001-04-22

    We describe a five-month-old male infant with Coffin-Siris syndrome, the so-called Dandy-Walker variant (hypoplasia of the cerebellar vermis with cystic dilatation of the fourth ventricle, but without enlargement of the posterior fossa), and partial agenesis of the corpus callosum. Dandy-Walker malformation and mega cisterna magna, but not Dandy-Walker variant, have been reported in Coffin-Siris syndrome. The presence of Dandy-Walker variant in the infant we described confirms that the full continuum of the Dandy-Walker complex can occur in Coffin-Siris syndrome. The yet unidentified gene(s) for the syndrome may be related to the development of the hindbrain. Copyright 2001 Wiley-Liss, Inc.

  4. A population-specific uncommon variant in GRIN3A associated with schizophrenia.

    Science.gov (United States)

    Takata, Atsushi; Iwayama, Yoshimi; Fukuo, Yasuhisa; Ikeda, Masashi; Okochi, Tomo; Maekawa, Motoko; Toyota, Tomoko; Yamada, Kazuo; Hattori, Eiji; Ohnishi, Tetsuo; Toyoshima, Manabu; Ujike, Hiroshi; Inada, Toshiya; Kunugi, Hiroshi; Ozaki, Norio; Nanko, Shinichiro; Nakamura, Kazuhiko; Mori, Norio; Kanba, Shigenobu; Iwata, Nakao; Kato, Tadafumi; Yoshikawa, Takeo

    2013-03-15

    Genome-wide association studies have successfully identified several common variants showing robust association with schizophrenia. However, individually, these variants only produce a weak effect. To identify genetic variants with larger effect sizes, increasing attention is now being paid to uncommon and rare variants. From the 1000 Genomes Project data, we selected 47 candidate single nucleotide variants (SNVs), which were: 1) uncommon (minor allele frequency way to discover risk variants with larger effects. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  5. CDKL5 variants: Improving our understanding of a rare neurologic disorder.

    Science.gov (United States)

    Hector, Ralph D; Kalscheuer, Vera M; Hennig, Friederike; Leonard, Helen; Downs, Jenny; Clarke, Angus; Benke, Tim A; Armstrong, Judith; Pineda, Mercedes; Bailey, Mark E S; Cobb, Stuart R

    2017-12-01

    To provide new insights into the interpretation of genetic variants in a rare neurologic disorder, CDKL5 deficiency, in the contexts of population sequencing data and an updated characterization of the CDKL5 gene. We analyzed all known potentially pathogenic CDKL5 variants by combining data from large-scale population sequencing studies with CDKL5 variants from new and all available clinical cohorts and combined this with computational methods to predict pathogenicity. The study has identified several variants that can be reclassified as benign or likely benign. With the addition of novel CDKL5 variants, we confirm that pathogenic missense variants cluster in the catalytic domain of CDKL5 and reclassify a purported missense variant as having a splicing consequence. We provide further evidence that missense variants in the final 3 exons are likely to be benign and not important to disease pathology. We also describe benign splicing and nonsense variants within these exons, suggesting that isoform hCDKL5_5 is likely to have little or no neurologic significance. We also use the available data to make a preliminary estimate of minimum incidence of CDKL5 deficiency. These findings have implications for genetic diagnosis, providing evidence for the reclassification of specific variants previously thought to result in CDKL5 deficiency. Together, these analyses support the view that the predominant brain isoform in humans (hCDKL5_1) is crucial for normal neurodevelopment and that the catalytic domain is the primary functional domain.

  6. Variant of Rett syndrome and CDKL5 gene

    DEFF Research Database (Denmark)

    Pini, Giorgio; Bigoni, Stefania; Engerström, Ingegerd Witt

    2012-01-01

    UNLABELLED: Rett syndrome (RTT) is a severe neurodevelopmental disorder affecting almost exclusively females. The Hanefeld variant, or early-onset seizure variant, has been associated with mutations in CDKL5 gene. AIMS: In recent years more than 60 patients with mutations in the CDKL5 gene have...... been described in the literature, but the cardiorespiratory phenotype has not been reported. Our aim is to describe clinical and autonomic features of these girls. METHODS: 10 girls with CDKL5 mutations and a diagnosis of Hanefeld variant have been evaluated on axiological and clinical aspects. In all...

  7. Gain-of-function HCN2 variants in genetic epilepsy.

    Science.gov (United States)

    Li, Melody; Maljevic, Snezana; Phillips, A Marie; Petrovski, Slave; Hildebrand, Michael S; Burgess, Rosemary; Mount, Therese; Zara, Federico; Striano, Pasquale; Schubert, Julian; Thiele, Holger; Nürnberg, Peter; Wong, Michael; Weisenberg, Judith L; Thio, Liu Lin; Lerche, Holger; Scheffer, Ingrid E; Berkovic, Samuel F; Petrou, Steven; Reid, Christopher A

    2018-02-01

    Genetic generalized epilepsy (GGE) is a common epilepsy syndrome that encompasses seizure disorders characterized by spike-and-wave discharges (SWDs). Pacemaker hyperpolarization-activated cyclic nucleotide-gated channels (HCN) are considered integral to SWD genesis, making them an ideal gene candidate for GGE. We identified HCN2 missense variants from a large cohort of 585 GGE patients, recruited by the Epilepsy Phenome-Genome Project (EPGP), and performed functional analysis using two-electrode voltage clamp recordings from Xenopus oocytes. The p.S632W variant was identified in a patient with idiopathic photosensitive occipital epilepsy and segregated in the family. This variant was also independently identified in an unrelated patient with childhood absence seizures from a European cohort of 238 familial GGE cases. The p.V246M variant was identified in a patient with photo-sensitive GGE and his father diagnosed with juvenile myoclonic epilepsy. Functional studies revealed that both p.S632W and p.V246M had an identical functional impact including a depolarizing shift in the voltage dependence of activation that is consistent with a gain-of-function. In contrast, no biophysical changes resulted from the introduction of common population variants, p.E280K and p.A705T, and the p.R756C variant from EPGP that did not segregate with disease. Our data suggest that HCN2 variants can confer susceptibility to GGE via a gain-of-function mechanism. © 2017 Wiley Periodicals, Inc.

  8. Effects of common hemoglobin variants on HbA1c measurements in China: results for α- and β-globin variants measured by six methods.

    Science.gov (United States)

    Xu, Anping; Chen, Weidong; Xia, Yong; Zhou, Yu; Ji, Ling

    2018-04-07

    HbA1c is a widely used biomarker for diabetes mellitus management. Here, we evaluated the accuracy of six methods for determining HbA1c values in Chinese patients with common α- and β-globin chains variants in China. Blood samples from normal subjects and individuals exhibiting hemoglobin variants were analyzed for HbA1c, using Sebia Capillarys 2 Flex Piercing (C2FP), Bio-Rad Variant II Turbo 2.0, Tosoh HLC-723 G8 (ver. 5.24), Arkray ADAMS A1c HA-8180V fast mode, Cobas c501 and Trinity Ultra2 systems. DNA sequencing revealed five common β-globin chain variants and three common α-globin chain variants. The most common variant was Hb E, followed by Hb New York, Hb J-Bangkok, Hb G-Coushatta, Hb Q-Thailand, Hb G-Honolulu, Hb Ube-2 and Hb G-Taipei. Variant II Turbo 2.0, Ultra2 and Cobas c501 showed good agreement with C2FP for most samples with variants. HLC-723 G8 yielded no HbA1c values for Hb J-Bangkok, Hb Q-Thailand and Hb G-Honolulu. Samples with Hb E, Hb G-Coushatta, Hb G-Taipei and Hb Ube-2 produced significant negative biases for HLC-723 G8. HA-8180V showed statistically significant differences for Hb E, Hb G-Coushatta, Hb G-Taipei, Hb Q-Thailand and Hb G-Honolulu. HA-8180V yielded no HbA1c values for Hb J-Bangkok. All methods showed good agreement for samples with Hb New York. Some common hemoglobin variants can interfere with HbA1c determination by the most popular methods in China.

  9. Re-Ranking Sequencing Variants in the Post-GWAS Era for Accurate Causal Variant Identification

    Science.gov (United States)

    Faye, Laura L.; Machiela, Mitchell J.; Kraft, Peter; Bull, Shelley B.; Sun, Lei

    2013-01-01

    Next generation sequencing has dramatically increased our ability to localize disease-causing variants by providing base-pair level information at costs increasingly feasible for the large sample sizes required to detect complex-trait associations. Yet, identification of causal variants within an established region of association remains a challenge. Counter-intuitively, certain factors that increase power to detect an associated region can decrease power to localize the causal variant. First, combining GWAS with imputation or low coverage sequencing to achieve the large sample sizes required for high power can have the unintended effect of producing differential genotyping error among SNPs. This tends to bias the relative evidence for association toward better genotyped SNPs. Second, re-use of GWAS data for fine-mapping exploits previous findings to ensure genome-wide significance in GWAS-associated regions. However, using GWAS findings to inform fine-mapping analysis can bias evidence away from the causal SNP toward the tag SNP and SNPs in high LD with the tag. Together these factors can reduce power to localize the causal SNP by more than half. Other strategies commonly employed to increase power to detect association, namely increasing sample size and using higher density genotyping arrays, can, in certain common scenarios, actually exacerbate these effects and further decrease power to localize causal variants. We develop a re-ranking procedure that accounts for these adverse effects and substantially improves the accuracy of causal SNP identification, often doubling the probability that the causal SNP is top-ranked. Application to the NCI BPC3 aggressive prostate cancer GWAS with imputation meta-analysis identified a new top SNP at 2 of 3 associated loci and several additional possible causal SNPs at these loci that may have otherwise been overlooked. This method is simple to implement using R scripts provided on the author's website. PMID:23950724

  10. Height-reducing variants and selection for short stature in Sardinia

    NARCIS (Netherlands)

    Zoledziewska, Magdalena; Sidore, Carlo; Chiang, Charleston W K; Sanna, Serena; Mulas, Antonella; Steri, Maristella; Busonero, Fabio; Marcus, Joseph H; Marongiu, Michele; Maschio, Andrea; Ortega Del Vecchyo, Diego; Floris, Matteo; Meloni, Antonella; Delitala, Alessandro; Concas, Maria Pina; Murgia, Federico; Biino, Ginevra; Vaccargiu, Simona; Nagaraja, Ramaiah; Lohmueller, Kirk E; Timpson, Nicholas J; Soranzo, Nicole; Tachmazidou, Ioanna; Dedoussis, George; Zeggini, Eleftheria; Uzzau, Sergio; Jones, Chris; Lyons, Robert; Angius, Andrea; Abecasis, Gonçalo R; Novembre, John; Schlessinger, David; Cucca, Francesco

    We report sequencing-based whole-genome association analyses to evaluate the impact of rare and founder variants on stature in 6,307 individuals on the island of Sardinia. We identify two variants with large effects. One variant, which introduces a stop codon in the GHR gene, is relatively frequent

  11. Human papillomavirus type-16 variants in Quechua aboriginals from Argentina.

    Science.gov (United States)

    Picconi, María Alejandra; Alonio, Lidia Virginia; Sichero, Laura; Mbayed, Viviana; Villa, Luisa Lina; Gronda, Jorge; Campos, Rodolfo; Teyssié, Angélica

    2003-04-01

    Cervical carcinoma is the leading cause of cancer death in Quechua indians from Jujuy (northwestern Argentina). To determine the prevalence of HPV-16 variants, 106 HPV-16 positive cervical samples were studied, including 33 low-grade squamous intraepithelial lesions (LSIL), 28 high-grade squamous intraepithelial lesions (HSIL), 9 invasive cervical cancer (ICC), and 36 samples from women with normal colposcopy and cytology. HPV genome variability was examined in the L1 and E6 genes by PCR-hybridization. In a subset of 20 samples, a LCR fragment was also analyzed by PCR-sequencing. Most variants belonged to the European branch with subtle differences that depended on the viral gene fragment studied. Only about 10% of the specimens had non-European variants, including eight Asian-American, two Asian, and one North-American-1. E6 gene analysis revealed that 43% of the samples were identical to HPV-16 prototype, while 57% corresponded to variants. Interestingly, the majority (87%) of normal smears had HPV-16 prototype, whereas variants were detected mainly in SIL and ICC. LCR sequencing yielded 80% of variants, including 69% of European, 19% Asian-American, and 12% Asian. We identified a new variant, the Argentine Quechua-51 (AQ-51), similar to B-14 plus two additional changes: G7842-->A and A7837-->C; phylogenetic inference allocated it in the Asian-American branch. The high proportion of European variants may reflect Spanish colonial influence on these native Inca descendants. The predominance of HPV-16 variants in pathologic samples when compared to normal controls could have implications for the natural history of cervical lesions. Copyright 2003 Wiley-Liss, Inc.

  12. Managing Process Variants in the Process Life Cycle

    NARCIS (Netherlands)

    Hallerbach, A.; Bauer, Th.; Reichert, M.U.

    2007-01-01

    When designing process-aware information systems, often variants of the same process have to be specified. Each variant then constitutes an adjustment of a particular process to specific requirements building the process context. Current Business Process Management (BPM) tools do not adequately

  13. Genetics Home Reference: GM2-gangliosidosis, AB variant

    Science.gov (United States)

    ... Resources Genetic Testing (1 link) Genetic Testing Registry: Tay-Sachs disease, variant AB General Information from MedlinePlus (5 links) ... AB variant Activator Deficiency/GM2 Gangliosidosis Activator-deficient Tay-Sachs disease GM2 Activator Deficiency Disease GM2 gangliosidosis, type AB ...

  14. [Hemoglobin variants in Colombian patients referred to discard hemoglobinopathies].

    Science.gov (United States)

    Romero-Sánchez, Consuelo; Gómez Gutiérrez, Alberto; Duarte, Yurani; Amazo, Constanza; Manosalva, Clara; Chila M, Lorena; Casas-Gómez, María Consuelo; Briceño Balcázar, Ignacio

    2015-10-01

    Oxygen transport is altered in hemoglobinopathies. To study the distribution of hemoglobinopathies in Andean subjects without African ancestry. We analyzed blood samples of 1,407 subjects aged 18 to 59 years (58% females), living in the central Andean region of Colombia, referred to discard hemoglobinopathies. The frequency and type of hemoglobinopathy was established by capillary and agarose gel electrophoresis. The frequency of hemoglobinopathies was 34.5% and higher among females. The structural variants found were: AS-heterozygous hemoglobin (8.1%), homozygous SS (3.7%), heterozygous SC (2.2%), AC heterozygotes (0.5%) and heterozygous AE (0.3%). Quantitative variants found were Hb A-Beta thalassemia (13.91%) and Hb H (0.06%), Beta-thalassemia heterozygotes C (0.88%), S-Beta thalassemia heterozygotes (6.07%) and compound heterozygous SC/Beta thalassemia (0.25%), with a persistence of fetal hemoglobin 0. Composite thalassemia was also found in 31%. All techniques showed good correlation and capillary electrophoresis demonstrated a greater detection of hemoglobin variants. The frequency of hemoglobin variants in the analyzed population was high, which is an important public health indicator. The most common hemoglobin variant was HbA/Increased structural Hb A2 and the mos frequent structural hemoglobinopathy was sickle cell trait. Capillary electrophoresis can discern any Hb variants present in the population.

  15. Genetics in psychiatry: common variant association studies

    Directory of Open Access Journals (Sweden)

    Buxbaum Joseph D

    2010-03-01

    Full Text Available Abstract Many psychiatric conditions and traits are associated with significant heritability. Genetic risk for psychiatric conditions encompass rare variants, identified due to major effect, as well as common variants, the latter analyzed by association analyses. We review guidelines for common variant association analyses, undertaking after assessing evidence of heritability. We highlight the importance of: suitably large sample sizes; an experimental design that controls for ancestry; careful data cleaning; correction for multiple testing; small P values for positive findings; assessment of effect size for positive findings; and, inclusion of an independent replication sample. We also note the importance of a critical discussion of any prior findings, biological follow-up where possible, and a means of accessing the raw data.

  16. Hemoglobin Variants: Biochemical Properties and Clinical Correlates

    Science.gov (United States)

    Thom, Christopher S.; Dickson, Claire F.; Gell, David A.; Weiss, Mitchell J.

    2013-01-01

    Diseases affecting hemoglobin synthesis and function are extremely common worldwide. More than 1000 naturally occurring human hemoglobin variants with single amino acid substitutions throughout the molecule have been discovered, mainly through their clinical and/or laboratory manifestations. These variants alter hemoglobin structure and biochemical properties with physiological effects ranging from insignificant to severe. Studies of these mutations in patients and in the laboratory have produced a wealth of information on hemoglobin biochemistry and biology with significant implications for hematology practice. More generally, landmark studies of hemoglobin performed over the past 60 years have established important paradigms for the disciplines of structural biology, genetics, biochemistry, and medicine. Here we review the major classes of hemoglobin variants, emphasizing general concepts and illustrative examples. PMID:23388674

  17. Genetics Home Reference: Ohdo syndrome, Say-Barber-Biesecker-Young-Simpson variant

    Science.gov (United States)

    ... SBBYS variant Ohdo syndrome, Say-Barber-Biesecker-Young-Simpson variant Printable PDF Open All Close All Enable ... collapse boxes. Description The Say-Barber-Biesecker-Young-Simpson (SBBYS) variant of Ohdo syndrome is a rare ...

  18. Warty Carcinoma Penis: An Uncommon Variant

    Directory of Open Access Journals (Sweden)

    Sushma Thapa

    2017-01-01

    Full Text Available Penile carcinoma frequency varies widely in different parts of the world and comprises 1–10% of all the malignancies in males. Majority of the cases of penile carcinoma are squamous cell carcinoma of penis comprising 60% to 70% of all cases. Warty carcinoma of penis is an unusual neoplasm and a variant of penile squamous cell carcinoma comprising 5%–10% of all the variants. The other histological variants include basaloid, verrucous, papillary, sarcomatous, mixed, and adenosquamous carcinoma. The various histological entities with an exophytic papillary lesions including warty carcinoma are together referred to as the “verruciform” group of neoplasms. The warty carcinoma has to be differentiated from these lesions and is typically distinguished by histological features of hyperkeratosis, arborescent papillomatosis, acanthosis, and prominent koilocytosis with nuclear pleomorphism. We present a case of 65-year-old male with growth measuring 6×4 cm in the penis who underwent total penectomy and was diagnosed as warty carcinoma penis.

  19. Cryptanalysis of RSA and its variants

    CERN Document Server

    Hinek, M Jason

    2009-01-01

    Thirty years after RSA was first publicized, it remains an active research area. Although several good surveys exist, they are either slightly outdated or only focus on one type of attack. Offering an updated look at this field, Cryptanalysis of RSA and Its Variants presents the best known mathematical attacks on RSA and its main variants, including CRT-RSA, multi-prime RSA, and multi-power RSA. Divided into three parts, the book first introduces RSA and reviews the mathematical background needed for the majority of attacks described in the remainder of the text. It then brings together all of the most popular mathematical attacks on RSA and its variants. For each attack presented, the author includes a mathematical proof if possible or a mathematical justification for attacks that rely on assumptions. For the attacks that cannot be proven, he gives experimental evidence to illustrate their practical effectiveness. Focusing on mathematical attacks that exploit the structure of RSA and specific parameter choic...

  20. Numerically-quantified two dimensionality of microstructure evolution accompanying variant selection of FePd

    International Nuclear Information System (INIS)

    Ueshima, N; Yoshiya, M; Yasuda, H; Fukuda, T; Kakeshita, T

    2015-01-01

    Through three-dimensional (3D) simulations of microstructure evolution by phase-field modeling (PFM), microstructures have been quantified during their time evolution by an image processing technique with particular attention to the shape of variants in the course of variant selection. It is found that the emerging variants exhibit planar shapes rather than 3D shapes due to the elastic field around the variants arising upon disorder-to-order transition to the L1 0 phase. The two-dimensionality is more pronounced as variant selection proceeds. Although three equivalent variants compete for dominance under an external field, one of the three variants vanishes before final competition occurs between the remaining variants, which can be explained by the elastic strain energy. These numerical analyses provide better understanding of the microstructure evolution in a more quantitative manner, including the small influence of the third variant, and the results obtained confirm that the understanding of variant selection obtained from two-dimensional (2D) simulations by PFM is valid. (paper)

  1. Assessment of Functional Effects of Unclassified Genetic Variants

    NARCIS (Netherlands)

    Couch, Fergus J.; Rasmussen, Lene Juel; Hofstra, Robert; Monteiro, Alvaro N. A.; Greenblatt, Marc S.; de Wind, Niels

    2008-01-01

    Inherited predisposition to disease is often linked to reduced activity of a disease associated gene product. Thus, quantitation of the influence of inherited variants on gene function can potentially be used to predict the disease relevance of these variants. While many disease genes have been

  2. Assessment of Functional Effects of Unclassified Genetic Variants

    NARCIS (Netherlands)

    Couch, Fergus J.; Rasmussen, Lene Juel; Hofstra, Robert; Monteiro, Alvaro N. A.; Greenblatt, Marc S.; de Wind, Niels

    Inherited predisposition to disease is often linked to reduced activity of a disease associated gene product. Thus, quantitation of the influence of inherited variants on gene function can potentially be used to predict the disease relevance of these variants. While many disease genes have been

  3. Canine parvovirus: the worldwide occurrence of antigenic variants.

    Science.gov (United States)

    Miranda, Carla; Thompson, Gertrude

    2016-09-01

    The most important enteric virus infecting canids is canine parvovirus type 2 (CPV-2). CPV is the aetiologic agent of a contagious disease, mainly characterized by clinical gastroenteritis signs in younger dogs. CPV-2 emerged as a new virus in the late 1970s, which could infect domestic dogs, and became distributed in the global dog population within 2 years. A few years later, the virus's original type was replaced by a new genetic and antigenic variant, called CPV-2a. Around 1984 and 2000, virus variants with the single change to Asp or Glu in the VP2 residue 426 were detected (sometimes termed CPV-2b and -2c). The genetic and antigenic changes in the variants have also been correlated with changes in their host range; in particular, in the ability to replicate in cats and also host range differences in canine and other tissue culture cells. CPV-2 variants have been circulating among wild carnivores and have been well-documented in several countries around the world. Here, we have reviewed and summarized the current information about the worldwide distribution and evolution of CPV-2 variants since they emerged, as well as the host ranges they are associated with.

  4. Delineation of concentration ranges and longitudinal changes of human plasma protein variants.

    Directory of Open Access Journals (Sweden)

    Olgica Trenchevska

    Full Text Available Human protein diversity arises as a result of alternative splicing, single nucleotide polymorphisms (SNPs and posttranslational modifications. Because of these processes, each protein can exists as multiple variants in vivo. Tailored strategies are needed to study these protein variants and understand their role in health and disease. In this work we utilized quantitative mass spectrometric immunoassays to determine the protein variants concentration of beta-2-microglobulin, cystatin C, retinol binding protein, and transthyretin, in a population of 500 healthy individuals. Additionally, we determined the longitudinal concentration changes for the protein variants from four individuals over a 6 month period. Along with the native forms of the four proteins, 13 posttranslationally modified variants and 7 SNP-derived variants were detected and their concentration determined. Correlations of the variants concentration with geographical origin, gender, and age of the individuals were also examined. This work represents an important step toward building a catalog of protein variants concentrations and examining their longitudinal changes.

  5. Migraine Variants in Children

    Science.gov (United States)

    ... Headaches in Children FAQ Migraine Variants In Children Children Get Migraines Too! Learn More Migraine Information Find Help Doctors & Resources Get Connected Join the Conversation Follow Us on Social Media Company About News Resources Privacy Policy Contact Phone: ...

  6. Listeners' processing of a given reduced word pronunciation variant directly reflects their exposure to this variant: Evidence from native listeners and learners of French.

    Science.gov (United States)

    Brand, Sophie; Ernestus, Mirjam

    2018-05-01

    In casual conversations, words often lack segments. This study investigates whether listeners rely on their experience with reduced word pronunciation variants during the processing of single segment reduction. We tested three groups of listeners in a lexical decision experiment with French words produced either with or without word-medial schwa (e.g., /ʀvy/ and /ʀvy/ for revue). Participants also rated the relative frequencies of the two pronunciation variants of the words. If the recognition accuracy and reaction times (RTs) for a given listener group correlate best with the frequencies of occurrence holding for that given listener group, recognition is influenced by listeners' exposure to these variants. Native listeners' relative frequency ratings correlated well with their accuracy scores and RTs. Dutch advanced learners' accuracy scores and RTs were best predicted by their own ratings. In contrast, the accuracy and RTs from Dutch beginner learners of French could not be predicted by any relative frequency rating; the rating task was probably too difficult for them. The participant groups showed behaviour reflecting their difference in experience with the pronunciation variants. Our results strongly suggest that listeners store the frequencies of occurrence of pronunciation variants, and consequently the variants themselves.

  7. The pathogenicity of genetic variants previously associated with left ventricular non-compaction

    DEFF Research Database (Denmark)

    Abbasi, Yeganeh; Jabbari, Javad; Jabbari, Reza

    2016-01-01

    BACKGROUND: Left ventricular non-compaction (LVNC) is a rare cardiomyopathy. Many genetic variants have been associated with LVNC. However, the number of the previous LVNC-associated variants that are common in the background population remains unknown. The aim of this study was to provide...... an updated list of previously reported LVNC-associated variants with biologic description and investigate the prevalence of LVNC variants in healthy general population to find false-positive LVNC-associated variants. METHODS AND RESULTS: The Human Gene Mutation Database and PubMed were systematically...... searched to identify all previously reported LVNC-associated variants. Thereafter, the Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC), that both represent the background population, was searched for all variants. Four in silico prediction tools were assessed to determine...

  8. Network perturbation by recurrent regulatory variants in cancer.

    Directory of Open Access Journals (Sweden)

    Kiwon Jang

    2017-03-01

    Full Text Available Cancer driving genes have been identified as recurrently affected by variants that alter protein-coding sequences. However, a majority of cancer variants arise in noncoding regions, and some of them are thought to play a critical role through transcriptional perturbation. Here we identified putative transcriptional driver genes based on combinatorial variant recurrence in cis-regulatory regions. The identified genes showed high connectivity in the cancer type-specific transcription regulatory network, with high outdegree and many downstream genes, highlighting their causative role during tumorigenesis. In the protein interactome, the identified transcriptional drivers were not as highly connected as coding driver genes but appeared to form a network module centered on the coding drivers. The coding and regulatory variants associated via these interactions between the coding and transcriptional drivers showed exclusive and complementary occurrence patterns across tumor samples. Transcriptional cancer drivers may act through an extensive perturbation of the regulatory network and by altering protein network modules through interactions with coding driver genes.

  9. Variants at the 9p21 locus and melanoma risk

    International Nuclear Information System (INIS)

    Maccioni, Livia; Rachakonda, Panduranga Sivaramakrishna; Bermejo, Justo Lorenzo; Planelles, Dolores; Requena, Celia; Hemminki, Kari; Nagore, Eduardo; Kumar, Rajiv

    2013-01-01

    The influence of variants at the 9p21 locus on melanoma risk has been reported through investigation of CDKN2A variants through candidate gene approach as well as by genome wide association studies (GWAS). In the present study we genotyped, 25 SNPs that tag 273 variants on chromosome 9p21 in 837 melanoma cases and 1154 controls from Spain. Ten SNPs were selected based on previous associations, reported in GWAS, with either melanocytic nevi or melanoma risk or both. The other 15 SNPs were selected to fine map the CDKN2A gene region. All the 10 variants selected from the GWAS showed statistically significant association with melanoma risk. Statistically significant association with melanoma risk was also observed for the carriers of the variant T-allele of rs3088440 (540 C>T) at the 3’ UTR of CDKN2A gene with an OR 1.52 (95% CI 1.14-2.04). Interaction analysis between risk associated polymorphisms and previously genotyped MC1R variants, in the present study, did not show any statistically significant association. Statistical significant association was observed for the interaction between phototypes and the rs10811629 (located in intron 5 of MTAP). The strongest association was observed between the homozygous carrier of the A–allele and phototype II with an OR of 15.93 (95% CI 5.34-47.54). Our data confirmed the association of different variants at chromosome 9p21 with melanoma risk and we also found an association of a variant with skin phototypes

  10. Spatial distributions of Pseudomonas fluorescens colony variants in mixed-culture biofilms.

    Science.gov (United States)

    Workentine, Matthew L; Wang, Siyuan; Ceri, Howard; Turner, Raymond J

    2013-07-28

    The emergence of colony morphology variants in structured environments is being recognized as important to both niche specialization and stress tolerance. Pseudomonas fluorescens demonstrates diversity in both its natural environment, the rhizosphere, and in laboratory grown biofilms. Sub-populations of these variants within a biofilm have been suggested as important contributors to antimicrobial stress tolerance given their altered susceptibility to various agents. As such it is of interest to determine how these variants might be distributed in the biofilm environment. Here we present an analysis of the spatial distribution of Pseudomonas fluorescens colony morphology variants in mixed-culture biofilms with the wildtype phenotype. These findings reveal that two variant colony morphotypes demonstrate a significant growth advantage over the wildtype morphotype in the biofilm environment. The two variant morphotypes out-grew the wildtype across the entire biofilm and this occurred within 24 h and was maintained through to 96 h. This competitive advantage was not observed in homogeneous broth culture. The significant advantage that the variants demonstrate in biofilm colonization over the wildtype denotes the importance of this phenotype in structured environments.

  11. Genomic constitution of an H-2:Tla variant leukemia.

    Science.gov (United States)

    Shen, F W; Chaganti, R S; Doucette, L A; Litman, G W; Steinmetz, M; Hood, L; Boyse, E A

    1984-10-01

    A TL+ leukemia of a (B6 X A)F1 hybrid mouse (H-2b/H-2a) was previously subjected to immunoselection against H-2a by passage in (B6 X A.SW)F1 mice (H-2b/H-2s). A variant leukemia line was obtained that serologically lacked not only the H-2a phenotype but also the TL phenotype determined by the linked cis Tlaa allele of strain A. The H-2b phenotype and the TL phenotype of the Tlab allele of the B6 strain, which is expressed only by leukemia cells, were retained by the variant. Southern blotting with an H-2 cDNA probe that identifies restriction fragment polymorphisms distinguishing alleles of the H-2 and Tla regions of the B6 and A strains indicates that both the H-2a and Tlaa alleles are missing from the genome of this H-2a:Tlaa negative variant. Since the variant has two apparently unaltered chromosomes 17, where the H-2:Tla complex is situated, and since the intensity of bands in Southern blotting is suggestive of H-2b homozygosity, it is considered that loss of the H-2a:Tlaa haplotype by the variant was accompanied by duplication of the H-2b:Tlab haplotype. The implied change from heterozygosity to homozygosity that the variant has undergone with respect to H-2:Tla was not paralleled by a similar change at the three other loci tested, since the variant retained heterozygosity for Pep-3 (chromosome 1), Gpi-1 (chromosome 7), and Es-1 (chromosome 8).

  12. Efficient utilization of rare variants for detection of disease-related genomic regions.

    Directory of Open Access Journals (Sweden)

    Lei Zhang

    2010-12-01

    Full Text Available When testing association between rare variants and diseases, an efficient analytical approach involves considering a set of variants in a genomic region as the unit of analysis. One factor complicating this approach is that the vast majority of rare variants in practical applications are believed to represent background neutral variation. As a result, analyzing a single set with all variants may not represent a powerful approach. Here, we propose two alternative strategies. In the first, we analyze the subsets of rare variants exhaustively. In the second, we categorize variants selectively into two subsets: one in which variants are overrepresented in cases, and the other in which variants are overrepresented in controls. When the proportion of neutral variants is moderate to large we show, by simulations, that the both proposed strategies improve the statistical power over methods analyzing a single set with total variants. When applied to a real sequencing association study, the proposed methods consistently produce smaller p-values than their competitors. When applied to another real sequencing dataset to study the difference of rare allele distributions between ethnic populations, the proposed methods detect the overrepresentation of variants between the CHB (Chinese Han in Beijing and YRI (Yoruba people of Ibadan populations with small p-values. Additional analyses suggest that there is no difference between the CHB and CHD (Chinese Han in Denver datasets, as expected. Finally, when applied to the CHB and JPT (Japanese people in Tokyo populations, existing methods fail to detect any difference, while it is detected by the proposed methods in several regions.

  13. Changes in classification of genetic variants in BRCA1 and BRCA2.

    Science.gov (United States)

    Kast, Karin; Wimberger, Pauline; Arnold, Norbert

    2018-02-01

    Classification of variants of unknown significance (VUS) in the breast cancer genes BRCA1 and BRCA2 changes with accumulating evidence for clinical relevance. In most cases down-staging towards neutral variants without clinical significance is possible. We searched the database of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) for changes in classification of genetic variants as an update to our earlier publication on genetic variants in the Centre of Dresden. Changes between 2015 and 2017 were recorded. In the group of variants of unclassified significance (VUS, Class 3, uncertain), only changes of classification towards neutral genetic variants were noted. In BRCA1, 25% of the Class 3 variants (n = 2/8) changed to Class 2 (likely benign) and Class 1 (benign). In BRCA2, in 50% of the Class 3 variants (n = 16/32), a change to Class 2 (n = 10/16) or Class 1 (n = 6/16) was observed. No change in classification was noted in Class 4 (likely pathogenic) and Class 5 (pathogenic) genetic variants in both genes. No up-staging from Class 1, Class 2 or Class 3 to more clinical significance was observed. All variants with a change in classification in our cohort were down-staged towards no clinical significance by a panel of experts of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). Prevention in families with Class 3 variants should be based on pedigree based risks and should not be guided by the presence of a VUS.

  14. Identifying genetic variants that affect viability in large cohorts.

    Directory of Open Access Journals (Sweden)

    Hakhamanesh Mostafavi

    2017-09-01

    Full Text Available A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Adult Health and Aging (GERA cohort and to the parents of participants in the UK Biobank. Across the genome, we found only a few common variants with large effects on age-specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late-onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence 1 of 42 traits, we detected a number of strong signals. In participants of the UK Biobank of British ancestry, we found that variants that delay puberty timing are associated with a longer parental life span (P~6.2 × 10-6 for fathers and P~2.0 × 10-3 for mothers, consistent with epidemiological studies. Similarly, variants associated with later age at first birth are associated with a longer maternal life span (P~1.4 × 10-3. Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease (CAD, body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. We also found marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of CAD and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical data sets can be used to learn about selection effects in contemporary humans.

  15. Protein variants in Hiroshima and Nagasaki: tales of two cities.

    Science.gov (United States)

    Neel, J V; Satoh, C; Smouse, P; Asakawa, J; Takahashi, N; Goriki, K; Fujita, M; Kageoka, T; Hazama, R

    1988-12-01

    The results of 1,465,423 allele product determinations based on blood samples from Hiroshima and Nagasaki, involving 30 different proteins representing 32 different gene products, are analyzed in a variety of ways, with the following conclusions: (1) Sibships and their parents are included in the sample. Our analysis reveals that statistical procedures designed to reduce the sample to equivalent independent genomes do not in population comparisons compensate for the familial cluster effect of rare variants. Accordingly, the data set was reduced to one representative of each sibship (937,427 allele products). (2) Both chi 2-type contrasts and a genetic distance measure (delta) reveal that rare variants (P less than .01) are collectively as effective as polymorphisms in establishing genetic differences between the two cities. (3) We suggest that rare variants that individually exhibit significant intercity differences are probably the legacy of tribal private polymorphisms that occurred during prehistoric times. (4) Despite the great differences in the known histories of the two cities, both the overall frequency of rare variants and the number of different rare variants are essentially identical in the two cities. (5) The well-known differences in locus variability are confirmed, now after adjustment for sample size differences for the various locus products; in this large series we failed to detect variants at only three of 29 loci for which sample size exceeded 23,000. (6) The number of alleles identified per locus correlates positively with subunit molecular weight. (7) Loci supporting genetic polymorphisms are characterized by more rare variants than are loci at which polymorphisms were not encountered. (8) Loci whose products do not appear to be essential for health support more variants than do loci the absence of whose product is detrimental to health. (9) There is a striking excess of rare variants over the expectation under the neutral mutation

  16. Following of erosive wash of soil in variants with different intercrops

    Directory of Open Access Journals (Sweden)

    Barbora Badalíková

    2010-01-01

    Full Text Available In a pilot experiment established in a sugar beet growing region the erosive washing away of soil was studied in the years 2006 to 2008. The area is located at an altitude of 246 m with the long-term mean precipitation of 500 mm and the mean annual temperature of 8.4 °C. The soils are classified as Chernozem, moderately heavy, loamy, with a good supply of nutrients, humus content of 2.30 % and an alkaline soil reaction. Slope gradient is 12 %, exposition is NE. To study the role of intercrops in erosion control, three variants were established after the harvest of the main crop, two variants with different intercrops and one (control with no intercrop. These were Variant 1 with Secale cereale L. var. multicaule METZG. ex ALEF., a non-freezing intercrop, Variant 2 with cluster mallow (Malva verticillata L., a freezing intercrop, and a control variant with no intercrop. In Variant 1 Secale cereale L. var. multicaule was desiccated with the herbicide Roundup in early spring. All the variants involved maize as the main crop. In variants 1 and 2, maize was sown in intercrop residues after seedbed preparation by Vario and a compactor. In Variant 3 maize was sown after conventional seedbed preparation. For assessment of soil conditions soil samples were taken to determine soil physical and chemical properties and water content in the soil. Soil loss by erosion was determined using specially-designed pockets. Erosive washing away of soil was monitored during the entire growing season of maize. The variants in which intercrops were used were found very effective in soil erosion control. In Variant 3 (control without surface crop residues, the washing away of soil was recorded with each heavy torrential rain. During the all years the total amount of soil loss by erosion in this treatment was 2.25 t . ha−1.

  17. Hepatitis E Virus Variant in Farmed Mink, Denmark

    DEFF Research Database (Denmark)

    Krog, Jesper Schak; Breum, Solvej Østergaard; Jensen, Trine Hammer

    2013-01-01

    Hepatitis E virus (HEV) is a zoonotic virus for which pigs are the primary animal reservoir. To investigate whether HEV occurs in mink in Denmark, we screened feces and tissues from domestic and wild mink. Our finding of a novel HEV variant supports previous findings of HEV variants in a variety...

  18. Efficient population-scale variant analysis and prioritization with VAPr.

    Science.gov (United States)

    Birmingham, Amanda; Mark, Adam M; Mazzaferro, Carlo; Xu, Guorong; Fisch, Kathleen M

    2018-04-06

    With the growing availability of population-scale whole-exome and whole-genome sequencing, demand for reproducible, scalable variant analysis has spread within genomic research communities. To address this need, we introduce the Python package VAPr (Variant Analysis and Prioritization). VAPr leverages existing annotation tools ANNOVAR and MyVariant.info with MongoDB-based flexible storage and filtering functionality. It offers biologists and bioinformatics generalists easy-to-use and scalable analysis and prioritization of genomic variants from large cohort studies. VAPr is developed in Python and is available for free use and extension under the MIT License. An install package is available on PyPi at https://pypi.python.org/pypi/VAPr, while source code and extensive documentation are on GitHub at https://github.com/ucsd-ccbb/VAPr. kfisch@ucsd.edu.

  19. IL10 low-frequency variants in Behçet's disease patients.

    Science.gov (United States)

    Matos, Mafalda; Xavier, Joana M; Abrantes, Patrícia; Sousa, Inês; Rei, Nádia; Davatchi, Fereydoun; Shahram, Farhad; Jesus, Gorete; Barcelos, Filipe; Vedes, Joana; Salgado, Manuel; Abdollahi, Bahar Sadeghi; Nadji, Abdolhadi; Moraes-Fontes, Maria Francisca; Shafiee, Niloofar Mojarad; Ghaderibarmi, Fahmida; Vaz Patto, José; Crespo, Jorge; Oliveira, Sofia A

    2017-05-01

    To explain the missing heritability after the genome-wide association studies era, sequencing studies allow the identification of low-frequency variants with a stronger effect on disease risk. Common variants in the interleukin 10 gene (IL10) have been consistently associated with Behçet's disease (BD) and the goal of this study is to investigate the role of low-frequency IL10 variants in BD susceptibility. To identify IL10 low-frequency variants, a discovery group of 50 Portuguese BD patients were Sanger-sequenced in a 7.7 kb genomic region encompassing the complete IL10 gene, 0.9 kb upstream and 2 kb downstream, and two conserved regions in the putative promoter. To assess if the novel variants are BD- and/or Portuguese-specific, they were assayed in an additional group of BD patients (26 Portuguese and 964 Iranian) and controls (104 Portuguese and 823 Iranian). Rare IL10 coding variants were not detected in BD patients, but we identified 28 known single nucleotide polymorphisms with minor allele frequencies ranging from 0.010 to 0.390, and five novel non-coding variants in five heterozygous cases. ss836185595, located in the IL10 3' untranslated region, was also detected in one Iranian control individual and therefore is not specific to BD. The remaining novel IL10 variants (ss836185596 and ss836185602 in intron 3, ss836185598 and ss836185604 in the putative promoter region) were not found in the replication dataset. This study highlights the importance of screening the whole gene and regulatory regions when searching for novel variants associated with complex diseases, and the need to develop bioinformatics tools to predict the functional impact of non-coding variants and statistical tests which incorporate these predictions. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  20. Two Novel Variants Affecting CDKL5 Transcript Associated with Epileptic Encephalopathy.

    Science.gov (United States)

    Neupauerová, Jana; Štěrbová, Katalin; Vlčková, Markéta; Sebroňová, Věra; Maříková, Tat'ána; Krůtová, Marcela; David, Staněk; Kršek, Pavel; Žaliová, Markéta; Seeman, Pavel; Laššuthová, Petra

    2017-10-01

    Variants in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been reported as being etiologically associated with early infantile epileptic encephalopathy type 2 (EIEE2). We report on two patients, a boy and a girl, with EIEE2 that present with early onset epilepsy, hypotonia, severe intellectual disability, and poor eye contact. Massively parallel sequencing (MPS) of a custom-designed gene panel for epilepsy and epileptic encephalopathy containing 112 epilepsy-related genes was performed. Sanger sequencing was used to confirm the novel variants. For confirmation of the functional consequence of an intronic CDKL5 variant in patient 2, an RNA study was done. DNA sequencing revealed de novo variants in CDKL5, a c.2578C>T (p. Gln860*) present in a hemizygous state in a 3-year-old boy, and a potential splice site variant c.463+5G>A in heterozygous state in a 5-year-old girl. Multiple in silico splicing algorithms predicted a highly reduced splice site score for c.463+5G>A. A subsequent mRNA study confirmed an aberrant shorter transcript lacking exon 7. Our data confirmed that variants in the CDKL5 are associated with EIEE2. There is credible evidence that the novel identified variants are pathogenic and, therefore, are likely the cause of the disease in the presented patients. In one of the patients a stop codon variant is predicted to produce a truncated protein, and in the other patient an intronic variant results in aberrant splicing.

  1. Common genetic variants influence human subcortical brain structures

    Science.gov (United States)

    Hibar, Derrek P.; Stein, Jason L.; Renteria, Miguel E.; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S.; Armstrong, Nicola J.; Bernard, Manon; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brown, Andrew A.; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L.; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Olde Loohuis, Loes M.; Luciano, Michelle; Macare, Christine; Mather, Karen A.; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L.; Roiz-Santiañez, Roberto; Rose, Emma J.; Salami, Alireza; Sämann, Philipp G.; Schmaal, Lianne; Schork, Andrew J.; Shin, Jean; Strike, Lachlan T.; Teumer, Alexander; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; Walters, Raymond K.; Westlye, Lars T.; Whelan, Christopher D.; Winkler, Anderson M.; Zwiers, Marcel P.; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M. H.; Hartberg, Cecilie B.; Haukvik, Unn K.; Heister, Angelien J. G. A. M.; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C. M.; Lopez, Lorna M.; Makkinje, Remco R. R.; Matarin, Mar; Naber, Marlies A. M.; McKay, D. Reese; Needham, Margaret; Nugent, Allison C.; Pütz, Benno; Royle, Natalie A.; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S. L.; van Hulzen, Kimm J. E.; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A.; Bastin, Mark E.; Brodaty, Henry; Bulayeva, Kazima B.; Carless, Melanie A.; Cichon, Sven; Corvin, Aiden; Curran, Joanne E.; Czisch, Michael; de Zubicaray, Greig I.; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D.; Erk, Susanne; Fedko, Iryna O.; Ferrucci, Luigi; Foroud, Tatiana M.; Fox, Peter T.; Fukunaga, Masaki; Gibbs, J. Raphael; Göring, Harald H. H.; Green, Robert C.; Guelfi, Sebastian; Hansell, Narelle K.; Hartman, Catharina A.; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G.; Heslenfeld, Dirk J.; Hoekstra, Pieter J.; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Liu, Xinmin; Longo, Dan L.; McMahon, Katie L.; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W.; Mostert, Jeanette C.; Mühleisen, Thomas W.; Nalls, Michael A.; Nichols, Thomas E.; Nilsson, Lars G.; Nöthen, Markus M.; Ohi, Kazutaka; Olvera, Rene L.; Perez-Iglesias, Rocio; Pike, G. Bruce; Potkin, Steven G.; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D.; Rujescu, Dan; Schnell, Knut; Schofield, Peter R.; Smith, Colin; Steen, Vidar M.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Turner, Jessica A.; Valdés Hernández, Maria C.; van ’t Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J. A.; van Tol, Marie-Jose; Veltman, Dick J.; Wassink, Thomas H.; Westman, Eric; Zielke, Ronald H.; Zonderman, Alan B.; Ashbrook, David G.; Hager, Reinmar; Lu, Lu; McMahon, Francis J.; Morris, Derek W.; Williams, Robert W.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Cahn, Wiepke; Calhoun, Vince D.; Cavalleri, Gianpiero L.; Crespo-Facorro, Benedicto; Dale, Anders M.; Davies, Gareth E.; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C.; Espeseth, Thomas; Gollub, Randy L.; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S.; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W. J. H.; Roffman, Joshua L.; Sisodiya, Sanjay M.; Smoller, Jordan W.; van Bokhoven, Hans; van Haren, Neeltje E. M.; Völzke, Henry; Walter, Henrik; Weiner, Michael W.; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A.; Blangero, John; Boomsma, Dorret I.; Brouwer, Rachel M.; Cannon, Dara M.; Cookson, Mark R.; de Geus, Eco J. C.; Deary, Ian J.; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E.; Francks, Clyde; Glahn, David C.; Grabe, Hans J.; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E.; Jönsson, Erik G.; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S.; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M.; Ophoff, Roel A.; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S.; Saykin, Andrew J.; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M.; Weale, Michael E.; Weinberger, Daniel R.; Adams, Hieab H. H.; Launer, Lenore J.; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L.; Becker, James T.; Yanek, Lisa; van der Lee, Sven J.; Ebling, Maritza; Fischl, Bruce; Longstreth, W. T.; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N.; van Duijn, Cornelia M.; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C.; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M. Arfan; Martin, Nicholas G.; Wright, Margaret J.; Schumann, Gunter; Franke, Barbara; Thompson, Paul M.; Medland, Sarah E.

    2015-01-01

    The highly complex structure of the human brain is strongly shaped by genetic influences1. Subcortical brain regions form circuits with cortical areas to coordinate movement2, learning, memory3 and motivation4, and altered circuits can lead to abnormal behaviour and disease2. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume5 and intracranial volume6. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10−33; 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability inhuman brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. PMID:25607358

  2. Common genetic variants influence human subcortical brain structures.

    Science.gov (United States)

    Hibar, Derrek P; Stein, Jason L; Renteria, Miguel E; Arias-Vasquez, Alejandro; Desrivières, Sylvane; Jahanshad, Neda; Toro, Roberto; Wittfeld, Katharina; Abramovic, Lucija; Andersson, Micael; Aribisala, Benjamin S; Armstrong, Nicola J; Bernard, Manon; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brown, Andrew A; Chakravarty, M Mallar; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; den Braber, Anouk; Giddaluru, Sudheer; Goldman, Aaron L; Grimm, Oliver; Guadalupe, Tulio; Hass, Johanna; Woldehawariat, Girma; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Olde Loohuis, Loes M; Luciano, Michelle; Macare, Christine; Mather, Karen A; Mattheisen, Manuel; Milaneschi, Yuri; Nho, Kwangsik; Papmeyer, Martina; Ramasamy, Adaikalavan; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rose, Emma J; Salami, Alireza; Sämann, Philipp G; Schmaal, Lianne; Schork, Andrew J; Shin, Jean; Strike, Lachlan T; Teumer, Alexander; van Donkelaar, Marjolein M J; van Eijk, Kristel R; Walters, Raymond K; Westlye, Lars T; Whelan, Christopher D; Winkler, Anderson M; Zwiers, Marcel P; Alhusaini, Saud; Athanasiu, Lavinia; Ehrlich, Stefan; Hakobjan, Marina M H; Hartberg, Cecilie B; Haukvik, Unn K; Heister, Angelien J G A M; Hoehn, David; Kasperaviciute, Dalia; Liewald, David C M; Lopez, Lorna M; Makkinje, Remco R R; Matarin, Mar; Naber, Marlies A M; McKay, D Reese; Needham, Margaret; Nugent, Allison C; Pütz, Benno; Royle, Natalie A; Shen, Li; Sprooten, Emma; Trabzuni, Daniah; van der Marel, Saskia S L; van Hulzen, Kimm J E; Walton, Esther; Wolf, Christiane; Almasy, Laura; Ames, David; Arepalli, Sampath; Assareh, Amelia A; Bastin, Mark E; Brodaty, Henry; Bulayeva, Kazima B; Carless, Melanie A; Cichon, Sven; Corvin, Aiden; Curran, Joanne E; Czisch, Michael; de Zubicaray, Greig I; Dillman, Allissa; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Fedko, Iryna O; Ferrucci, Luigi; Foroud, Tatiana M; Fox, Peter T; Fukunaga, Masaki; Gibbs, J Raphael; Göring, Harald H H; Green, Robert C; Guelfi, Sebastian; Hansell, Narelle K; Hartman, Catharina A; Hegenscheid, Katrin; Heinz, Andreas; Hernandez, Dena G; Heslenfeld, Dirk J; Hoekstra, Pieter J; Holsboer, Florian; Homuth, Georg; Hottenga, Jouke-Jan; Ikeda, Masashi; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Kanai, Ryota; Keil, Maria; Kent, Jack W; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Liu, Xinmin; Longo, Dan L; McMahon, Katie L; Meisenzahl, Eva; Melle, Ingrid; Mohnke, Sebastian; Montgomery, Grant W; Mostert, Jeanette C; Mühleisen, Thomas W; Nalls, Michael A; Nichols, Thomas E; Nilsson, Lars G; Nöthen, Markus M; Ohi, Kazutaka; Olvera, Rene L; Perez-Iglesias, Rocio; Pike, G Bruce; Potkin, Steven G; Reinvang, Ivar; Reppermund, Simone; Rietschel, Marcella; Romanczuk-Seiferth, Nina; Rosen, Glenn D; Rujescu, Dan; Schnell, Knut; Schofield, Peter R; Smith, Colin; Steen, Vidar M; Sussmann, Jessika E; Thalamuthu, Anbupalam; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Valdés Hernández, Maria C; van 't Ent, Dennis; van der Brug, Marcel; van der Wee, Nic J A; van Tol, Marie-Jose; Veltman, Dick J; Wassink, Thomas H; Westman, Eric; Zielke, Ronald H; Zonderman, Alan B; Ashbrook, David G; Hager, Reinmar; Lu, Lu; McMahon, Francis J; Morris, Derek W; Williams, Robert W; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Cahn, Wiepke; Calhoun, Vince D; Cavalleri, Gianpiero L; Crespo-Facorro, Benedicto; Dale, Anders M; Davies, Gareth E; Delanty, Norman; Depondt, Chantal; Djurovic, Srdjan; Drevets, Wayne C; Espeseth, Thomas; Gollub, Randy L; Ho, Beng-Choon; Hoffmann, Wolfgang; Hosten, Norbert; Kahn, René S; Le Hellard, Stephanie; Meyer-Lindenberg, Andreas; Müller-Myhsok, Bertram; Nauck, Matthias; Nyberg, Lars; Pandolfo, Massimo; Penninx, Brenda W J H; Roffman, Joshua L; Sisodiya, Sanjay M; Smoller, Jordan W; van Bokhoven, Hans; van Haren, Neeltje E M; Völzke, Henry; Walter, Henrik; Weiner, Michael W; Wen, Wei; White, Tonya; Agartz, Ingrid; Andreassen, Ole A; Blangero, John; Boomsma, Dorret I; Brouwer, Rachel M; Cannon, Dara M; Cookson, Mark R; de Geus, Eco J C; Deary, Ian J; Donohoe, Gary; Fernández, Guillén; Fisher, Simon E; Francks, Clyde; Glahn, David C; Grabe, Hans J; Gruber, Oliver; Hardy, John; Hashimoto, Ryota; Hulshoff Pol, Hilleke E; Jönsson, Erik G; Kloszewska, Iwona; Lovestone, Simon; Mattay, Venkata S; Mecocci, Patrizia; McDonald, Colm; McIntosh, Andrew M; Ophoff, Roel A; Paus, Tomas; Pausova, Zdenka; Ryten, Mina; Sachdev, Perminder S; Saykin, Andrew J; Simmons, Andy; Singleton, Andrew; Soininen, Hilkka; Wardlaw, Joanna M; Weale, Michael E; Weinberger, Daniel R; Adams, Hieab H H; Launer, Lenore J; Seiler, Stephan; Schmidt, Reinhold; Chauhan, Ganesh; Satizabal, Claudia L; Becker, James T; Yanek, Lisa; van der Lee, Sven J; Ebling, Maritza; Fischl, Bruce; Longstreth, W T; Greve, Douglas; Schmidt, Helena; Nyquist, Paul; Vinke, Louis N; van Duijn, Cornelia M; Xue, Luting; Mazoyer, Bernard; Bis, Joshua C; Gudnason, Vilmundur; Seshadri, Sudha; Ikram, M Arfan; Martin, Nicholas G; Wright, Margaret J; Schumann, Gunter; Franke, Barbara; Thompson, Paul M; Medland, Sarah E

    2015-04-09

    The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

  3. Functional significance of SPINK1 promoter variants in chronic pancreatitis.

    Science.gov (United States)

    Derikx, Monique H M; Geisz, Andrea; Kereszturi, Éva; Sahin-Tóth, Miklós

    2015-05-01

    Chronic pancreatitis is a progressive inflammatory disorder of the pancreas, which often develops as a result of genetic predisposition. Some of the most frequently identified risk factors affect the serine protease inhibitor Kazal type 1 (SPINK1) gene, which encodes a trypsin inhibitor responsible for protecting the pancreas from premature trypsinogen activation. Recent genetic and functional studies indicated that promoter variants in the SPINK1 gene might contribute to disease risk in carriers. Here, we investigated the functional effects of 17 SPINK1 promoter variants using luciferase reporter gene expression assay in four different cell lines, including three pancreatic acinar cell lines (rat AR42J with or without dexamethasone-induced differentiation and mouse 266-6) and human embryonic kidney 293T cells. We found that most variants caused relatively small changes in promoter activity. Surprisingly, however, we observed significant variations in the effects of the promoter variants in the different cell lines. Only four variants exhibited consistently reduced promoter activity in all acinar cell lines, confirming previous reports that variants c.-108G>T, c.-142T>C, and c.-147A>G are risk factors for chronic pancreatitis and identifying c.-52G>T as a novel risk variant. In contrast, variant c.-215G>A, which is linked with the disease-associated splice-site mutation c.194 + 2T>C, caused increased promoter activity, which may mitigate the overall effect of the pathogenic haplotype. Our study lends further support to the notion that sequence evaluation of the SPINK1 promoter region in patients with chronic pancreatitis is justified as part of the etiological investigation. Copyright © 2015 the American Physiological Society.

  4. Differences in the Load-Velocity Profile Between 4 Bench-Press Variants.

    Science.gov (United States)

    García-Ramos, Amador; Pestaña-Melero, Francisco Luis; Pérez-Castilla, Alejandro; Rojas, Francisco Javier; Haff, Guy Gregory

    2018-03-01

    To compare the load-velocity relationship between 4 variants of the bench-press (BP) exercise. The full load-velocity relationship of 30 men was evaluated by means of an incremental loading test starting at 17 kg and progressing to the individual 1-repetition maximum (1RM) in 4 BP variants: concentric-only BP, concentric-only BP throw (BPT), eccentric-concentric BP, and eccentric-concentric BPT. A strong and fairly linear relationship between mean velocity (MV) and %1RM was observed for the 4 BP variants (r 2  > .96 for pooled data and r 2  > .98 for individual data). The MV associated with each %1RM was significantly higher in the eccentric-concentric technique than in the concentric-only technique. The only significant difference between the BP and BPT variants was the higher MV with the light to moderate loads (20-70%1RM) in the BPT using the concentric-only technique. MV was significantly and positively correlated between the 4 BP variants (r = .44-.76), which suggests that the subjects with higher velocities for each %1RM in 1 BP variant also tend to have higher velocities for each %1RM in the 3 other BP variants. These results highlight the need for obtaining specific equations for each BP variant and the existence of individual load-velocity profiles.

  5. A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

    Science.gov (United States)

    Karbassi, Izabela; Maston, Glenn A; Love, Angela; DiVincenzo, Christina; Braastad, Corey D; Elzinga, Christopher D; Bright, Alison R; Previte, Domenic; Zhang, Ke; Rowland, Charles M; McCarthy, Michele; Lapierre, Jennifer L; Dubois, Felicita; Medeiros, Katelyn A; Batish, Sat Dev; Jones, Jeffrey; Liaquat, Khalida; Hoffman, Carol A; Jaremko, Malgorzata; Wang, Zhenyuan; Sun, Weimin; Buller-Burckle, Arlene; Strom, Charles M; Keiles, Steven B; Higgins, Joseph J

    2016-01-01

    We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies collected from internal and external sources. Scores were calculated by trained scientists using a quantitative framework that assigned differential weighting to these five types of data. We performed descriptive and comparative statistics on the dataset and tested interobserver concordance among the trained scientists. Private variants defined as variants found within single families (n = 5,182), were either VUS (80.5%; n = 4,169) or likely pathogenic (19.5%; n = 1,013). The remaining variants (n = 6,712) were VUS (38.4%; n = 2,577) or likely benign/benign (34.7%; n = 2,327) or likely pathogenic/pathogenic (26.9%, n = 1,808). Exact agreement between the trained scientists on the final variant score was 98.5% [95% confidence interval (CI) (98.0, 98.9)] with an interobserver consistency of 97% [95% CI (91.5, 99.4)]. Variant scores were stable and showed increasing odds of being in agreement with new data when re-evaluated periodically. This carefully curated, standardized variant pathogenicity scoring system provides reliable pathogenicity scores for DNA variants encountered in a clinical laboratory setting. © 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

  6. Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA.

    Science.gov (United States)

    Schrader, Kasmintan A; Cheng, Donavan T; Joseph, Vijai; Prasad, Meera; Walsh, Michael; Zehir, Ahmet; Ni, Ai; Thomas, Tinu; Benayed, Ryma; Ashraf, Asad; Lincoln, Annie; Arcila, Maria; Stadler, Zsofia; Solit, David; Hyman, David M; Hyman, David; Zhang, Liying; Klimstra, David; Ladanyi, Marc; Offit, Kenneth; Berger, Michael; Robson, Mark

    2016-01-01

    Tumor genetic sequencing identifies potentially targetable genetic alterations with therapeutic implications. Analysis has concentrated on detecting tumor-specific variants, but recognition of germline variants may prove valuable as well. To estimate the burden of germline variants identified through routine clinical tumor sequencing. Patients with advanced cancer diagnoses eligible for studies of targeted agents at Memorial Sloan Kettering Cancer Center are offered tumor-normal sequencing with MSK-IMPACT, a 341-gene panel. We surveyed the germline variants seen in 187 overlapping genes with Mendelian disease associations in 1566 patients who had undergone tumor profiling between March and October 2014. The number of presumed pathogenic germline variants (PPGVs) and variants of uncertain significance per person in 187 genes associated with single-gene disorders and the proportions of individuals with PPGVs in clinically relevant gene subsets, in genes consistent with known tumor phenotypes, and in genes with evidence of second somatic hits in their tumors. The mean age of the 1566 patients was 58 years, and 54% were women. Presumed pathogenic germline variants in known Mendelian disease-associated genes were identified in 246 of 1566 patients (15.7%; 95% CI, 14.0%-17.6%), including 198 individuals with mutations in genes associated with cancer susceptibility. Germline findings in cancer susceptibility genes were concordant with the individual's cancer type in only 81 of 198 cases (40.9%; 95% CI, 34.3%-47.9%). In individuals with PPGVs retained in the tumor, somatic alteration of the other allele was seen in 39 of 182 cases (21.4%; 95% CI, 16.1%-28.0%), of which 13 cases did not show a known correlation of the germline mutation and a known syndrome. Mutations in non-cancer-related Mendelian disease genes were seen in 55 of 1566 cases (3.5%; 95% CI, 27.1%-45.4%). Almost every individual had more than 1 variant of uncertain significance (1565 of 1566 patients; 99

  7. Extension twin variant selection during uniaxial compression of a magnesium alloy

    DEFF Research Database (Denmark)

    Pei, Y.; Godfrey, A.; Jiang, J.

    2012-01-01

    is also observed in that smaller grains are less likely to contain lower ranked twin variants. For both 5% and 10% compression no clear relationship exists between the volume fraction of each twin variant in a given grain population and the Schmid factor for the twin variant. A positive linear......Samples of the magnesium alloy AZ31 have been deformed by compression to strains of 5% and 10% and microstructural observations made to investigate the activation of specific {1 0 1¯ 2} extension twin variants. The twinning has been analyzed on a grain-by-grain basis for more than 260 grains...... to determine both the number of extension twin variants in each grain, and the volume fraction of each. At 5% strain approx. 30% of the grains contain twins corresponding to variants with the third or lower ranked Schmid factor, with the fraction increasing to 40% after 10% compression. A grain size effect...

  8. DeepPVP: phenotype-based prioritization of causative variants using deep learning

    KAUST Repository

    Boudellioua, Imene

    2018-05-02

    Background: Prioritization of variants in personal genomic data is a major challenge. Recently, computational methods that rely on comparing phenotype similarity have shown to be useful to identify causative variants. In these methods, pathogenicity prediction is combined with a semantic similarity measure to prioritize not only variants that are likely to be dysfunctional but those that are likely involved in the pathogenesis of a patient\\'s phenotype. Results: We have developed DeepPVP, a variant prioritization method that combined automated inference with deep neural networks to identify the likely causative variants in whole exome or whole genome sequence data. We demonstrate that DeepPVP performs significantly better than existing methods, including phenotype-based methods that use similar features. DeepPVP is freely available at https://github.com/bio-ontology-research-group/phenomenet-vp Conclusions: DeepPVP further improves on existing variant prioritization methods both in terms of speed as well as accuracy.

  9. A geometric framework for evaluating rare variant tests of association.

    Science.gov (United States)

    Liu, Keli; Fast, Shannon; Zawistowski, Matthew; Tintle, Nathan L

    2013-05-01

    The wave of next-generation sequencing data has arrived. However, many questions still remain about how to best analyze sequence data, particularly the contribution of rare genetic variants to human disease. Numerous statistical methods have been proposed to aggregate association signals across multiple rare variant sites in an effort to increase statistical power; however, the precise relation between the tests is often not well understood. We present a geometric representation for rare variant data in which rare allele counts in case and control samples are treated as vectors in Euclidean space. The geometric framework facilitates a rigorous classification of existing rare variant tests into two broad categories: tests for a difference in the lengths of the case and control vectors, and joint tests for a difference in either the lengths or angles of the two vectors. We demonstrate that genetic architecture of a trait, including the number and frequency of risk alleles, directly relates to the behavior of the length and joint tests. Hence, the geometric framework allows prediction of which tests will perform best under different disease models. Furthermore, the structure of the geometric framework immediately suggests additional classes and types of rare variant tests. We consider two general classes of tests which show robustness to noncausal and protective variants. The geometric framework introduces a novel and unique method to assess current rare variant methodology and provides guidelines for both applied and theoretical researchers. © 2013 Wiley Periodicals, Inc.

  10. CEACAM6 gene variants in inflammatory bowel disease.

    Science.gov (United States)

    Glas, Jürgen; Seiderer, Julia; Fries, Christoph; Tillack, Cornelia; Pfennig, Simone; Weidinger, Maria; Beigel, Florian; Olszak, Torsten; Lass, Ulrich; Göke, Burkhard; Ochsenkühn, Thomas; Wolf, Christiane; Lohse, Peter; Müller-Myhsok, Bertram; Diegelmann, Julia; Czamara, Darina; Brand, Stephan

    2011-04-29

    The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) acts as a receptor for adherent-invasive E. coli (AIEC) and its ileal expression is increased in patients with Crohn's disease (CD). Given its contribution to the pathogenesis of CD, we aimed to investigate the role of genetic variants in the CEACAM6 region in patients with inflammatory bowel diseases (IBD). In this study, a total of 2,683 genomic DNA samples (including DNA from 858 CD patients, 475 patients with ulcerative colitis (UC), and 1,350 healthy, unrelated controls) was analyzed for eight CEACAM6 SNPs (rs10415946, rs1805223 = p.Pro42Pro, rs4803507, rs4803508, rs11548735 = p.Gly239Val, rs7246116 = pHis260His, rs2701, rs10416839). In addition, a detailed haplotype analysis and genotype-phenotype analysis were performed. Overall, our genotype analysis did not reveal any significant association of the investigated CEACAM6 SNPs and haplotypes with CD or UC susceptibility, although certain CEACAM6 SNPs modulated CEACAM6 expression in intestinal epithelial cell lines. Despite its function as receptor of AIEC in ileal CD, we found no association of the CEACAM6 SNPs with ileal or ileocolonic CD. Moreover, there was no evidence of epistasis between the analyzed CEACAM6 variants and the main CD-associated NOD2, IL23R and ATG16L1 variants. This study represents the first detailed analysis of CEACAM6 variants in IBD patients. Despite its important role in bacterial attachment in ileal CD, we could not demonstrate a role for CEACAM6 variants in IBD susceptibility or regarding an ileal CD phenotype. Further functional studies are required to analyze if these gene variants modulate ileal bacterial attachment.

  11. CEACAM6 gene variants in inflammatory bowel disease.

    Directory of Open Access Journals (Sweden)

    Jürgen Glas

    Full Text Available BACKGROUND: The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6 acts as a receptor for adherent-invasive E. coli (AIEC and its ileal expression is increased in patients with Crohn's disease (CD. Given its contribution to the pathogenesis of CD, we aimed to investigate the role of genetic variants in the CEACAM6 region in patients with inflammatory bowel diseases (IBD. METHODOLOGY: In this study, a total of 2,683 genomic DNA samples (including DNA from 858 CD patients, 475 patients with ulcerative colitis (UC, and 1,350 healthy, unrelated controls was analyzed for eight CEACAM6 SNPs (rs10415946, rs1805223 = p.Pro42Pro, rs4803507, rs4803508, rs11548735 = p.Gly239Val, rs7246116 = pHis260His, rs2701, rs10416839. In addition, a detailed haplotype analysis and genotype-phenotype analysis were performed. Overall, our genotype analysis did not reveal any significant association of the investigated CEACAM6 SNPs and haplotypes with CD or UC susceptibility, although certain CEACAM6 SNPs modulated CEACAM6 expression in intestinal epithelial cell lines. Despite its function as receptor of AIEC in ileal CD, we found no association of the CEACAM6 SNPs with ileal or ileocolonic CD. Moreover, there was no evidence of epistasis between the analyzed CEACAM6 variants and the main CD-associated NOD2, IL23R and ATG16L1 variants. CONCLUSIONS: This study represents the first detailed analysis of CEACAM6 variants in IBD patients. Despite its important role in bacterial attachment in ileal CD, we could not demonstrate a role for CEACAM6 variants in IBD susceptibility or regarding an ileal CD phenotype. Further functional studies are required to analyze if these gene variants modulate ileal bacterial attachment.

  12. Características morfoanatômicas da epiderme foliar de plantas variantes e não variantes somaclonais de bananeiras (Musa sp. Colla cv. Prata-anã cultivadas in vitro Morphoanatomical characteristics of the leaf epidermis of variant plants and somaclonal non-variants of banana trees (Musa sp. Colla cv. Prata-anã cultivated in vitro

    Directory of Open Access Journals (Sweden)

    Guilherme Araújo Lacerda

    2008-03-01

    Full Text Available A variação somaclonal corresponde ao aparecimento de plantas anormais durante o processo de multiplicação in vitro, principalmente relacionada à estatura, no caso o gigantismo. O objetivo deste trabalho foi averiguar as diferenças morfoanatômicas da epiderme foliar na tentativa de diferenciar as plantas de 'Prata-anã' em relação aos seus variantes somaclonais. A análise por microscopia eletrônica de varredura mostrou uma diferença significativa entre o diâmetro polar dos estômatos da 'Prata-anã' não variante e suas variantes, ambas em condições in vitro, observando-se que o mesmo não ocorre para as plantas in vivo. O número médio de estômatos é menor nas plantas variantes somaclonais, porém sem diferenças significativas a não ser para a planta PIII. A descamação de cera é evidente somente nas plantas variantes de ambos os materiais (in vitro e in vivo. Conclui-se que os caracteres morfoanatômicos da epiderme foliar, como densidade estomática, diâmetro estomático polar e a uniformidade da cera atuam como marcadores morfológicos para caracterizar as plantas micropropagadas de 'Prata-anã' em relação aos seus variantes somaclonais para a característica gigantismo.Somaclonal variation corresponds to the emergence of abnormal plants during the process of multiplication in vitro, mainly related to stature, in the case the gigantism. The aim of this work was to discover morphoanatomical differences of the leaf epidermis in an attempt to differentiate plants of "Prata-anã" from their somaclonal variants. Analysis by scanning electronic microscopy showed significant difference between the polar diameter of the stomata of the "Prata-anã" non-variant and its variants, both in vitro. The same does not happen for plants in vivo. The average number of stomata is lower in the somaclonal variant plants, but without significant differences except for plant PIII. Wax peeling is only evident in the variant plants of both the

  13. Impact of Pathogen Population Heterogeneity and Stress-Resistant Variants on Food Safety.

    Science.gov (United States)

    Abee, T; Koomen, J; Metselaar, K I; Zwietering, M H; den Besten, H M W

    2016-01-01

    This review elucidates the state-of-the-art knowledge about pathogen population heterogeneity and describes the genotypic and phenotypic analyses of persister subpopulations and stress-resistant variants. The molecular mechanisms underlying the generation of persister phenotypes and genetic variants are identified. Zooming in on Listeria monocytogenes, a comparative whole-genome sequence analysis of wild types and variants that enabled the identification of mutations in variants obtained after a single exposure to lethal food-relevant stresses is described. Genotypic and phenotypic features are compared to those for persistent strains isolated from food processing environments. Inactivation kinetics, models used for fitting, and the concept of kinetic modeling-based schemes for detection of variants are presented. Furthermore, robustness and fitness parameters of L. monocytogenes wild type and variants are used to model their performance in food chains. Finally, the impact of stress-resistant variants and persistence in food processing environments on food safety is discussed.

  14. BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

    NARCIS (Netherlands)

    Shimelis, Hermela; Mesman, Romy L. S.; Von Nicolai, Catharina; Ehlen, Asa; Guidugli, Lucia; Martin, Charlotte; Calléja, Fabienne M. G. R.; Meeks, Huong; Hallberg, Emily; Hinton, Jamie; Lilyquist, Jenna; Hu, Chunling; Aalfs, Cora M.; Aittomäki, Kristiina; Andrulis, Irene; Anton-Culver, Hoda; Arndt, Volker; Beckmann, Matthias W.; Benitez, Javier; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Borresen-Dale, Anne-Lise; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Broeks, Annegien; Brouwers, Barbara; Brüning, Thomas; Burwinkel, Barbara; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Cheng, Ching-Yu; Choi, Ji-Yeob; Collée, J. Margriet; Cox, Angela; Cross, Simon S.; Czene, Kamila; Darabi, Hatef; Dennis, Joe; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dunning, Alison M.; Fasching, Peter A.; Figueroa, Jonine; Flyger, Henrik; García-Closas, Montserrat; Giles, Graham G.; Glendon, Gord; Guénel, Pascal; Haiman, Christopher A.; Hall, Per; Hamann, Ute; Hartman, Mikael; Hogervorst, Frans B.; Hollestelle, Antoinette; Hopper, John L.; Ito, Hidemi; Jakubowska, Anna; Kang, Daehee; Kosma, Veli-Matti; Kristensen, Vessela; Lai, Kah-Nyin; Lambrechts, Diether; Marchand, Loic Le; Li, Jingmei; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Machackova, Eva; Mannermaa, Arto; Margolin, Sara; Marme, Frederik; Matsuo, Keitaro; Miao, Hui; Michailidou, Kyriaki; Milne, Roger L.; Muir, Kenneth; Neuhausen, Susan L.; Nevanlinna, Heli; Olson, Janet E.; Olswold, Curtis; Oosterwijk, Jan J. C.; Osorio, Ana; Peterlongo, Paolo; Peto, Julian; Pharoah, Paul D. P.; Pylkäs, Katri; Radice, Paolo; Rashid, Muhammad Usman; Rhenius, Valerie; Rudolph, Anja; Sangrajrang, Suleeporn; Sawyer, Elinor J.; Schmidt, Marjanka K.; Schoemaker, Minouk J.; Seynaeve, Caroline; Shah, Mitul; Shen, Chen-Yang; Shrubsole, Martha; Shu, Xiao-Ou; Slager, Susan; Southey, Melissa C.; Stram, Daniel O.; Swerdlow, Anthony; teo, Soo H.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; van Asperen, Christi J.; van der Kolk, Lizet E.; Wang, Qin; Winqvist, Robert; Wu, Anna H.; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Leary, Jennifer; Walker, Logan; Foretova, Lenka; Fostira, Florentia; Claes, Kathleen B. M.; Varesco, Liliana; Moghadasi, Setareh; Easton, Douglas F.; Spurdle, Amanda; Devilee, Peter; Vrieling, Harry; Monteiro, Alvaro N. A.; Goldgar, David E.; Carreira, Aura; Vreeswijk, Maaike P. G.; Couch, Fergus J.

    2017-01-01

    Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk

  15. Predicting effects of noncoding variants with deep learning-based sequence model.

    Science.gov (United States)

    Zhou, Jian; Troyanskaya, Olga G

    2015-10-01

    Identifying functional effects of noncoding variants is a major challenge in human genetics. To predict the noncoding-variant effects de novo from sequence, we developed a deep learning-based algorithmic framework, DeepSEA (http://deepsea.princeton.edu/), that directly learns a regulatory sequence code from large-scale chromatin-profiling data, enabling prediction of chromatin effects of sequence alterations with single-nucleotide sensitivity. We further used this capability to improve prioritization of functional variants including expression quantitative trait loci (eQTLs) and disease-associated variants.

  16. GBA Variants Influence Motor and Non-Motor Features of Parkinson's Disease.

    Science.gov (United States)

    Jesús, Silvia; Huertas, Ismael; Bernal-Bernal, Inmaculada; Bonilla-Toribio, Marta; Cáceres-Redondo, María Teresa; Vargas-González, Laura; Gómez-Llamas, Myriam; Carrillo, Fátima; Calderón, Enrique; Carballo, Manuel; Gómez-Garre, Pilar; Mir, Pablo

    2016-01-01

    The presence of mutations in glucocerebrosidase (GBA) gene is a known factor increasing the risk of developing Parkinson's disease (PD). Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson's patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021), earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013), as well as more prevalent motor and non-motor symptoms in patients carrying deleterious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non-motor symptoms as well as treatment-related motor complications could be influenced by GBA variants.

  17. GBA Variants Influence Motor and Non-Motor Features of Parkinson's Disease.

    Directory of Open Access Journals (Sweden)

    Silvia Jesús

    Full Text Available The presence of mutations in glucocerebrosidase (GBA gene is a known factor increasing the risk of developing Parkinson's disease (PD. Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson's patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021, earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013, as well as more prevalent motor and non-motor symptoms in patients carrying deleterious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non-motor symptoms as well as treatment-related motor complications could be influenced by GBA variants.

  18. VPA: an R tool for analyzing sequencing variants with user-specified frequency pattern

    Directory of Open Access Journals (Sweden)

    Hu Qiang

    2012-01-01

    Full Text Available Abstract Background The massive amounts of genetic variant generated by the next generation sequencing systems demand the development of effective computational tools for variant prioritization. Findings VPA (Variant Pattern Analyzer is an R tool for prioritizing variants with specified frequency pattern from multiple study subjects in next-generation sequencing study. The tool starts from individual files of variant and sequence calls and extract variants with user-specified frequency pattern across the study subjects of interest. Several position level quality criteria can be incorporated into the variant extraction. It can be used in studies with matched pair design as well as studies with multiple groups of subjects. Conclusions VPA can be used as an automatic pipeline to prioritize variants for further functional exploration and hypothesis generation. The package is implemented in the R language and is freely available from http://vpa.r-forge.r-project.org.

  19. Ossification variants of the femoral condyles are not associated with osteochondritis dissecans

    Energy Technology Data Exchange (ETDEWEB)

    Jans, L., E-mail: lennartjans@hotmail.com [Department of Radiology and Medical Imaging, Ghent University Hospital, De Pintelaan 185, 9000 Gent (Belgium); Jaremko, J., E-mail: jjaremko@gmail.com [Department of Radiology, University of Alberta Hospital, 8440-112 Street, Edmonton T6G 2B7, Alberta (Canada); Ditchfield, M., E-mail: Michael.ditchfield@southernhealth.org.au [Department of Radiology, Monash University Clayton Campus, Wellington Road, Clayton 3800, VIC (Australia); De Coninck, T., E-mail: Tinekedeconinck@ugent.be [Department of Radiology and Medical Imaging, Ghent University Hospital, De Pintelaan 185, 9000 Gent (Belgium); Huysse, W., E-mail: Wouter.huysse@ugent.be [Department of Radiology and Medical Imaging, Ghent University Hospital, De Pintelaan 185, 9000 Gent (Belgium); Moon, A., E-mail: Anna.moon@rch.org.au [Department of Radiology, Royal Children' s Hospital, Flemington Road, Parkville 3052, VIC (Australia); Verstraete, K., E-mail: Koenraad.verstraete@ugent.be [Department of Radiology and Medical Imaging, Ghent University Hospital, De Pintelaan 185, 9000 Gent (Belgium)

    2012-11-15

    Purpose: To determine if ossification variants of the femoral condyles involving the subchondral bone plate are associated with osteochondritis dissecans (OCD). Materials and methods: The prevalence of ossification variants of the unaffected femoral condyle in 116 patients (aged 9-14 years) with unicondylar OCD on MRI (magnetic resonance imaging) of the knee was compared to a control group of 579 patients (aged 9-14 years) without OCD. The evolution of the ossification variants in both groups was studied by reviewing follow-up MR imaging side by side with the baseline study. Results: The prevalence of ossification variants in the unaffected condyle in patients with OCD (12.9%) and in the control group of patients without OCD (12.6%) was similar (p = 0.88). Evolution of ossification variants to OCD was not seen on follow-up MRI examinations. All variants had decreased in size or were no longer visible. Conclusion: Ossification variants of the femoral condyle that involve the subchondral bone plate are not associated with OCD. Clinical relevance statement: Ossification variants are not associated with OCD, indicating that routine MRI follow-up in affected children is not mandatory.

  20. Ossification variants of the femoral condyles are not associated with osteochondritis dissecans

    International Nuclear Information System (INIS)

    Jans, L.; Jaremko, J.; Ditchfield, M.; De Coninck, T.; Huysse, W.; Moon, A.; Verstraete, K.

    2012-01-01

    Purpose: To determine if ossification variants of the femoral condyles involving the subchondral bone plate are associated with osteochondritis dissecans (OCD). Materials and methods: The prevalence of ossification variants of the unaffected femoral condyle in 116 patients (aged 9–14 years) with unicondylar OCD on MRI (magnetic resonance imaging) of the knee was compared to a control group of 579 patients (aged 9–14 years) without OCD. The evolution of the ossification variants in both groups was studied by reviewing follow-up MR imaging side by side with the baseline study. Results: The prevalence of ossification variants in the unaffected condyle in patients with OCD (12.9%) and in the control group of patients without OCD (12.6%) was similar (p = 0.88). Evolution of ossification variants to OCD was not seen on follow-up MRI examinations. All variants had decreased in size or were no longer visible. Conclusion: Ossification variants of the femoral condyle that involve the subchondral bone plate are not associated with OCD. Clinical relevance statement: Ossification variants are not associated with OCD, indicating that routine MRI follow-up in affected children is not mandatory.

  1. Evaluating how variants of floristic quality assessment indicate wetland condition.

    Science.gov (United States)

    Kutcher, Thomas E; Forrester, Graham E

    2018-03-28

    Biological indicators are useful tools for the assessment of ecosystem condition. Multi-metric and multi-taxa indicators may respond to a broader range of disturbances than simpler indicators, but their complexity can make them difficult to interpret, which is critical to indicator utility for ecosystem management. Floristic Quality Assessment (FQA) is an example of a biological assessment approach that has been widely tested for indicating freshwater wetland condition, but less attention has been given to clarifying the factors controlling its response. FQA quantifies the aggregate of vascular plant species tolerance to habitat degradation (conservatism), and model variants have incorporated species richness, abundance, and indigenity (native or non-native). To assess bias, we tested FQA variants in open-canopy freshwater wetlands against three independent reference measures, using practical vegetation sampling methods. FQA variants incorporating species richness did not correlate with our reference measures and were influenced by wetland size and hydrogeomorphic class. In contrast, FQA variants lacking measures of species richness responded linearly to reference measures quantifying individual and aggregate stresses, suggesting a broad response to cumulative degradation. FQA variants incorporating non-native species, and a variant additionally incorporating relative species abundance, improved performance over using only native species. We relate our empirical findings to ecological theory to clarify the functional properties and implications of the FQA variants. Our analysis indicates that (1) aggregate conservatism reliably declines with increased disturbance; (2) species richness has varying relationships with disturbance and increases with site area, confounding FQA response; and (3) non-native species signal human disturbance. We propose that incorporating species abundance can improve FQA site-level relevance with little extra sampling effort. Using our

  2. Family studies to find rare high risk variants in migraine.

    Science.gov (United States)

    Hansen, Rikke Dyhr; Christensen, Anne Francke; Olesen, Jes

    2017-12-01

    Migraine has long been known as a common complex disease caused by genetic and environmental factors. The pathophysiology and the specific genetic susceptibility are poorly understood. Common variants only explain a small part of the heritability of migraine. It is thought that rare genetic variants with bigger effect size may be involved in the disease. Since migraine has a tendency to cluster in families, a family approach might be the way to find these variants. This is also indicated by identification of migraine-associated loci in classical linkage-analyses in migraine families. A single migraine study using a candidate-gene approach was performed in 2010 identifying a rare mutation in the TRESK potassium channel segregating in a large family with migraine with aura, but this finding has later become questioned. The technologies of next-generation sequencing (NGS) now provides an affordable tool to investigate the genetic variation in the entire exome or genome. The family-based study design using NGS is described in this paper. We also review family studies using NGS that have been successful in finding rare variants in other common complex diseases in order to argue the promising application of a family approach to migraine. PubMed was searched to find studies that looked for rare genetic variants in common complex diseases through a family-based design using NGS, excluding studies looking for de-novo mutations, or using a candidate-gene approach and studies on cancer. All issues from Nature Genetics and PLOS genetics 2014, 2015 and 2016 (UTAI June) were screened for relevant papers. Reference lists from included and other relevant papers were also searched. For the description of the family-based study design using NGS an in-house protocol was used. Thirty-two successful studies, which covered 16 different common complex diseases, were included in this paper. We also found a single migraine study. Twenty-three studies found one or a few family specific

  3. Holographic representation of space-variant systems: system theory.

    Science.gov (United States)

    Marks Ii, R J; Krile, T F

    1976-09-01

    System theory for holographic representation of linear space-variant systems is derived. The utility of the resulting piecewise isoplanatic approximation (PIA) is illustrated by example application to the invariant system, ideal magnifier, and Fourier transformer. A method previously employed to holographically represent a space-variant system, the discrete approximation, is shown to be a special case of the PIA.

  4. Normal variants of skin in neonates

    Directory of Open Access Journals (Sweden)

    Kulkarni M

    1996-01-01

    Full Text Available 2221 consecutive live births taking place between March 1994 and February 1995 were evaluated for a minimum period of 5 days to note for the occurrence of various normal anatomical variants specially those of skin. Birth weight, gestational age, maternal age, socio-economic status and consanguinity were carefully recorded in all the cases. Mongolian spots (72%, Epstein pearls (43.8%, Milia (26.2% and Erythema toxicum (25.2%, were the common dermatological variants noted. Maturity of the babies and possibly genetic factors (consanguinity are important factors in their causation as ordered in our study.

  5. Variant Plasmodium ovale isolated from a patient infected in Ghana

    Directory of Open Access Journals (Sweden)

    Petersen Eskild

    2011-01-01

    Full Text Available Abstract Recent data have found that Plasmodium ovale can be separated in two distinct species: classic and variant P. ovale based on multilocus typing of different genes. This study presents a P. ovale isolate from a patient infected in Ghana together with an analysis of the small subunit RNA, cytochrome b, cytochrome c oxidase I, cysteine protease and lactate dehydrogenase genes, which show that the sample is a variant P. ovale and identical or highly similar to variant P. ovale isolated from humans in South-East Asia and Africa, and from a chimpanzee in Cameroon. The split between the variant and classic P. ovale is estimated to have occurred 1.7 million years ago.

  6. High-performance web services for querying gene and variant annotation.

    Science.gov (United States)

    Xin, Jiwen; Mark, Adam; Afrasiabi, Cyrus; Tsueng, Ginger; Juchler, Moritz; Gopal, Nikhil; Stupp, Gregory S; Putman, Timothy E; Ainscough, Benjamin J; Griffith, Obi L; Torkamani, Ali; Whetzel, Patricia L; Mungall, Christopher J; Mooney, Sean D; Su, Andrew I; Wu, Chunlei

    2016-05-06

    Efficient tools for data management and integration are essential for many aspects of high-throughput biology. In particular, annotations of genes and human genetic variants are commonly used but highly fragmented across many resources. Here, we describe MyGene.info and MyVariant.info, high-performance web services for querying gene and variant annotation information. These web services are currently accessed more than three million times permonth. They also demonstrate a generalizable cloud-based model for organizing and querying biological annotation information. MyGene.info and MyVariant.info are provided as high-performance web services, accessible at http://mygene.info and http://myvariant.info . Both are offered free of charge to the research community.

  7. Prebiotic Competition between Information Variants, With Low Error Catastrophe Risks

    Directory of Open Access Journals (Sweden)

    Radu Popa

    2015-07-01

    Full Text Available During competition for resources in primitive networks increased fitness of an information variant does not necessarily equate with successful elimination of its competitors. If variability is added fast to a system, speedy replacement of pre-existing and less-efficient forms of order is required as novel information variants arrive. Otherwise, the information capacity of the system fills up with information variants (an effect referred as “error catastrophe”. As the cost for managing the system’s exceeding complexity increases, the correlation between performance capabilities of information variants and their competitive success decreases, and evolution of such systems toward increased efficiency slows down. This impasse impedes the understanding of evolution in prebiotic networks. We used the simulation platform Biotic Abstract Dual Automata (BiADA to analyze how information variants compete in a resource-limited space. We analyzed the effect of energy-related features (differences in autocatalytic efficiency, energy cost of order, energy availability, transformation rates and stability of order on this competition. We discuss circumstances and controllers allowing primitive networks acquire novel information with minimal “error catastrophe” risks. We present a primitive mechanism for maximization of energy flux in dynamic networks. This work helps evaluate controllers of evolution in prebiotic networks and other systems where information variants compete.

  8. A systematic approach to assessing the clinical significance of genetic variants.

    Science.gov (United States)

    Duzkale, H; Shen, J; McLaughlin, H; Alfares, A; Kelly, M A; Pugh, T J; Funke, B H; Rehm, H L; Lebo, M S

    2013-11-01

    Molecular genetic testing informs diagnosis, prognosis, and risk assessment for patients and their family members. Recent advances in low-cost, high-throughput DNA sequencing and computing technologies have enabled the rapid expansion of genetic test content, resulting in dramatically increased numbers of DNA variants identified per test. To address this challenge, our laboratory has developed a systematic approach to thorough and efficient assessments of variants for pathogenicity determination. We first search for existing data in publications and databases including internal, collaborative and public resources. We then perform full evidence-based assessments through statistical analyses of observations in the general population and disease cohorts, evaluation of experimental data from in vivo or in vitro studies, and computational predictions of potential impacts of each variant. Finally, we weigh all evidence to reach an overall conclusion on the potential for each variant to be disease causing. In this report, we highlight the principles of variant assessment, address the caveats and pitfalls, and provide examples to illustrate the process. By sharing our experience and providing a framework for variant assessment, including access to a freely available customizable tool, we hope to help move towards standardized and consistent approaches to variant assessment. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Single-variant and multi-variant trend tests for genetic association with next-generation sequencing that are robust to sequencing error.

    Science.gov (United States)

    Kim, Wonkuk; Londono, Douglas; Zhou, Lisheng; Xing, Jinchuan; Nato, Alejandro Q; Musolf, Anthony; Matise, Tara C; Finch, Stephen J; Gordon, Derek

    2012-01-01

    As with any new technology, next-generation sequencing (NGS) has potential advantages and potential challenges. One advantage is the identification of multiple causal variants for disease that might otherwise be missed by SNP-chip technology. One potential challenge is misclassification error (as with any emerging technology) and the issue of power loss due to multiple testing. Here, we develop an extension of the linear trend test for association that incorporates differential misclassification error and may be applied to any number of SNPs. We call the statistic the linear trend test allowing for error, applied to NGS, or LTTae,NGS. This statistic allows for differential misclassification. The observed data are phenotypes for unrelated cases and controls, coverage, and the number of putative causal variants for every individual at all SNPs. We simulate data considering multiple factors (disease mode of inheritance, genotype relative risk, causal variant frequency, sequence error rate in cases, sequence error rate in controls, number of loci, and others) and evaluate type I error rate and power for each vector of factor settings. We compare our results with two recently published NGS statistics. Also, we create a fictitious disease model based on downloaded 1000 Genomes data for 5 SNPs and 388 individuals, and apply our statistic to those data. We find that the LTTae,NGS maintains the correct type I error rate in all simulations (differential and non-differential error), while the other statistics show large inflation in type I error for lower coverage. Power for all three methods is approximately the same for all three statistics in the presence of non-differential error. Application of our statistic to the 1000 Genomes data suggests that, for the data downloaded, there is a 1.5% sequence misclassification rate over all SNPs. Finally, application of the multi-variant form of LTTae,NGS shows high power for a number of simulation settings, although it can have

  10. Microcystic Variant of Urothelial Carcinoma

    Directory of Open Access Journals (Sweden)

    Anthony Kodzo-Grey Venyo

    2013-01-01

    Full Text Available Background. Microcystic variant of urothelial carcinoma is one of the new variants of urothelial carcinoma that was added to the WHO classification in 2004. Aims. To review the literature on microcystic variant of urothelial carcinoma. Methods. Various internet search engines were used to identify reported cases of the tumour. Results. Microscopic features of the tumour include: (i Conspicuous intracellular and intercellular lumina/microcysts encompassed by malignant urothelial or squamous cells. (ii The lumina are usually empty; may contain granular eosinophilic debris, mucin, or necrotic cells. (iii The cysts may be variable in size; round, or oval, up to 2 mm; lined by urothelium which are either flattened cells or low columnar cells however, they do not contain colonic epithelium or goblet cells; are infiltrative; invade the muscularis propria; mimic cystitis cystica and cystitis glandularis; occasionally exhibit neuroendocrine differentiation. (iv Elongated and irregular branching spaces are usually seen. About 17 cases of the tumour have been reported with only 2 patients who have survived. The tumour tends to be of high-grade and high-stage. There is no consensus opinion on the best option of treatment of the tumour. Conclusions. It would prove difficult at the moment to be dogmatic regarding its prognosis but it is a highly aggressive tumour. New cases of the tumour should be reported in order to document its biological behaviour.

  11. Diverse Functional Properties of Wilson Disease ATP7B Variants

    Science.gov (United States)

    Huster, Dominik; Kühne, Angelika; Bhattacharjee, Ashima; Raines, Lily; Jantsch, Vanessa; Noe, Johannes; Schirrmeister, Wiebke; Sommerer, Ines; Sabri, Osama; Berr, Frieder; Mössner, Joachim; Stieger, Bruno; Caca, Karel; Lutsenko, Svetlana

    2012-01-01

    BACKGROUND & AIMS Wilson disease is a severe disorder of copper metabolism caused by mutations in ATP7B, which encodes a copper-transporting adenosine triphosphatase. The disease presents with a variable phenotype that complicates the diagnostic process and treatment. Little is known about the mechanisms that contribute to the different phenotypes of the disease. METHODS We analyzed 28 variants of ATP7B from patients with Wilson disease that affected different functional domains; the gene products were expressed using the baculovirus expression system in Sf9 cells. Protein function was analyzed by measuring catalytic activity and copper (64Cu) transport into vesicles. We studied intracellular localization of variants of ATP7B that had measurable transport activities and were tagged with green fluorescent protein in mammalian cells using confocal laser scanning microscopy. RESULTS Properties of ATP7B variants with pathogenic amino-acid substitution varied greatly even if substitutions were in the same functional domain. Some variants had complete loss of catalytic and transport activity, whereas others lost transport activity but retained phosphor-intermediate formation or had partial losses of activity. In mammalian cells, transport-competent variants differed in stability and subcellular localization. CONCLUSIONS Variants in ATP7B associated with Wilson disease disrupt the protein’s transport activity, result in its mislocalization, and reduce its stability. Single assays are insufficient to accurately predict the effects of ATP7B variants the function of its product and development of Wilson disease. These findings will contribute to our understanding of genotype–phenotype correlation and mechanisms of disease pathogenesis. PMID:22240481

  12. Relation of genomic variants for Alzheimer disease dementia to common neuropathologies.

    Science.gov (United States)

    Farfel, Jose M; Yu, Lei; Buchman, Aron S; Schneider, Julie A; De Jager, Philip L; Bennett, David A

    2016-08-02

    To investigate the associations of previously reported Alzheimer disease (AD) dementia genomic variants with common neuropathologies. This is a postmortem study including 1,017 autopsied participants from 2 clinicopathologic cohorts. Analyses focused on 22 genomic variants associated with AD dementia in large-scale case-control genome-wide association study (GWAS) meta-analyses. The neuropathologic traits of interest were a pathologic diagnosis of AD according to NIA-Reagan criteria, macroscopic and microscopic infarcts, Lewy bodies (LB), and hippocampal sclerosis. For each variant, multiple logistic regression was used to investigate its association with neuropathologic traits, adjusting for age, sex, and subpopulation structure. We also conducted power analyses to estimate the sample sizes required to detect genome-wide significance (p dementia variants are not likely to be detected for association with pathologic AD with a sample size in excess of the largest GWAS meta-analyses of AD dementia. Many recently discovered genomic variants for AD dementia are not associated with the pathology of AD. Some genomic variants for AD dementia appear to be associated with other common neuropathologies. © 2016 American Academy of Neurology.

  13. Molecular characterization of a Xylanase-producing fungus isolated from fouled soil

    Directory of Open Access Journals (Sweden)

    Punniavan Sakthiselvan

    2014-12-01

    Full Text Available Xylanase (EC 3. 2. 1. 8, hydrolyzes xylo-oligosaccharides into D-xylose and required for complete hydrolysis of native cellulose and biomass conversion. It has broad range of applications in the pulp and paper, pharmaceutical and Agri-food industries. Fifty fungal species were isolated from the fouled soil around an oil refinery and screened for the production of xylanase enzyme by enrichment culture techniques. The isolated fungal strain was identified as Hypocrea lixii SS1 based on the results of biochemical tests and 18s rRNA sequencing. The phylogenetic tree was constructed using the MEGA 5 software. Further, Hypocrea lixii SS1 was tested for the ability to utilize the sunflower oil sludge (waste from the oil industry as the sole carbon source for xylanase production. The growth characteristics of Hypocrea lixii SS1 were also studied and maximum growth was found on the 7th day of incubation. The fungus showed a remarkable xylanase production of 38.9 U/mL. Xylanase was purified using a combination of 0-50% NH4SO2 precipitation, DEAE-sepharose and Sephacryl S-200 chromatography. Single peak obtained in RP-HPLC confirms the purity of xylanase. Further the enzyme produced was affirmed as xylanase with its molecular weight (29 kDa using SDS-PAGE.

  14. Ultrastructural studies on variants of Streptomyces SP-765 obtained after gamma irradiation

    International Nuclear Information System (INIS)

    Spasova, D.I.; Krystev, Kh.I.; Todorov, I.O.; Dzhedzheva, G.M.; Popov, M.S.

    1988-01-01

    The study has been carried out with two variants of Streptomyces SP-765, gray and olygosporous, obtained after 1000 Gy gamma irradiation of spore suspension from the initial strain. The gray variant has chains of spores which are oval or oblong with rounded-off edges. Sporulation is highly inhibited in the olygosporous variant. Eleven electron-microscopic pictures of ultrathin sections from colonies of the two variants are presented. The gray variant reveals the presence of a large number of lyzed cells, spores, and scarce vegetative cells; typical of the lyzed cells are the spherical and highly osmiophilic formations on the outer and inner surface of their cytoplasmic membrane. The oligosporous variant shows lyzed cells of various sizes, cells void of content with thick walls, relativelly small number of vegetative cells and individual wall-less cells, shperoplast and protoplast formation, lamellar membrane structure of nearly all cells. Both lyzed and vegetable cells have individual anomalous form containing daughter cells. The conclusion is made that gray and oligosporous variants of Streptomyces SP-765, obtained after irradiation of its spores, possess different ultrastructural organization

  15. Incidental copy-number variants identified by routine genome testing in a clinical population

    Science.gov (United States)

    Boone, Philip M.; Soens, Zachry T.; Campbell, Ian M.; Stankiewicz, Pawel; Cheung, Sau Wai; Patel, Ankita; Beaudet, Arthur L.; Plon, Sharon E.; Shaw, Chad A.; McGuire, Amy L.; Lupski, James R.

    2013-01-01

    Purpose Mutational load of susceptibility variants has not been studied on a genomic scale in a clinical population, nor has the potential to identify these mutations as incidental findings during clinical testing been systematically ascertained. Methods Array comparative genomic hybridization, a method for genome-wide detection of DNA copy-number variants, was performed clinically on DNA from 9,005 individuals. Copy-number variants encompassing or disrupting single genes were identified and analyzed for their potential to confer predisposition to dominant, adult-onset disease. Multigene copy-number variants affecting dominant, adult-onset cancer syndrome genes were also assessed. Results In our cohort, 83 single-gene copy-number variants affected 40 unique genes associated with dominant, adult-onset disorders and unrelated to the patients’ referring diagnoses (i.e., incidental) were found. Fourteen of these copy-number variants are likely disease-predisposing, 25 are likely benign, and 44 are of unknown clinical consequence. When incidental copy-number variants spanning up to 20 genes were considered, 27 copy-number variants affected 17 unique genes associated with dominant, adult-onset cancer predisposition. Conclusion Copy-number variants potentially conferring susceptibility to adult-onset disease can be identified as incidental findings during routine genome-wide testing. Some of these mutations may be medically actionable, enabling disease surveillance or prevention; however, most incidentally observed single-gene copy-number variants are currently of unclear significance to the patient. PMID:22878507

  16. Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms.

    Science.gov (United States)

    Marsh, Judith C W; Gutierrez-Rodrigues, Fernanda; Cooper, James; Jiang, Jie; Gandhi, Shreyans; Kajigaya, Sachiko; Feng, Xingmin; Ibanez, Maria Del Pilar F; Donaires, Flávia S; Lopes da Silva, João P; Li, Zejuan; Das, Soma; Ibanez, Maria; Smith, Alexander E; Lea, Nicholas; Best, Steven; Ireland, Robin; Kulasekararaj, Austin G; McLornan, Donal P; Pagliuca, Anthony; Callebaut, Isabelle; Young, Neal S; Calado, Rodrigo T; Townsley, Danielle M; Mufti, Ghulam J

    2018-01-09

    Biallelic germline mutations in RTEL1 (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of RTEL1 mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic RTEL1 mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n = 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n = 59). Twenty-three RTEL1 variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic RTEL1 variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, RTEL1 variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 3' telomeric overhangs were significantly eroded in 4. In summary, heterozygous RTEL1 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying RTEL1 variants. Pathogenicity assessment of heterozygous RTEL1 variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants.

  17. Reversion in variants from a duplication strain of Aspergillus nidulans

    International Nuclear Information System (INIS)

    Menezes, E.M.; Azevedo, J.L.

    1978-01-01

    Strains of Aspergillus nidulans with a chromosome segment in duplicate, one in normal position and one translocated to another chromosome, are unstable at mitosis. In addition to variants which result from deletions in either of the duplicate segments, which usually have improved morphology, they produce variants with deteriorated morphology. Three deteriorated variants reverted frequently to parental type morphology, both spontaneously and after ultra-violet treatment. Of six reversions analysed genetically, five were due to suppressors and one was probably due to back mutation. The suppressors segregated as single genes and were not linked to the mutation which they suppress. The instability of these so-called 'deteriorated' variants is discussed in relation to mitotic instability phenomena in A. nidulans. (orig.) [de

  18. Investigation of Exomic Variants Associated with Overall Survival in Ovarian Cancer

    DEFF Research Database (Denmark)

    Winham, Stacey J; Pirie, Ailith; Chen, Yian Ann

    2016-01-01

    ). Results: No individual variant reached genome-wide statistical significance. A SNP previously implicated to be associated with EOC risk and, to a lesser extent, survival, rs8170, showed the strongest evidence of association with survival and similar effect size estimates across sets (Pmeta=1.1E-6,HRSet1......=1.17,HRSet2= 1.14). Rare variants in ATG2B, an autophagy gene important for apoptosis, were significantly associated with survival after multiple testing correction (Pmeta = 1.1E-6; Pcorrected = 0.01). Conclusions: Common variant rs8170 and rare variants in ATG2B may be associated with EOC overall survival...

  19. Micromechanics of transformation-induced plasticity and variant coalescence

    International Nuclear Information System (INIS)

    Marketz, F.; Fischer, F.D.; University for Mining and Metallurgy, Leoben; Tanaka, K.

    1996-01-01

    Quantitative micromechanics descriptions of both transformation-induced plasticity (TRIP) associated with the martensitic transformation in an Fe-Ni alloy and of variant coalescence in a Cu-Al-Ni shape memory alloy are presented. The macroscopic deformation behavior of a polycrystalline aggregate as a result of the rearrangements within the crystallites is modelled with the help of a finite element based periodic microfield approach. In the case of TRIP the parent→martensite transformation is described by microscale thermodynamic and kinetic equations taking into account internal stress states. The simulation of a classical experiment on TRIP allows to quantify the Magee-effect and the Greenwood-Johnson effect. Furthermore, the development of the martensitic microstructure is studied with respect to the stress-assisted transformation of preferred variants. In the case of variant coalescence the strain energy due to internal stress states has an important influence on the mechanical behavior. Formulating the reorientation process on the size scale of self-accommodating plate groups in terms of the mobility of the boundaries between martensitic variants the macroscopic behavior in uniaxial tension is predicted by an incremental modelling procedure. Furthermore, influence of energy dissipation on the overall behavior is quantified. (orig.)

  20. TIAM1 variants improve clinical outcome in neuroblastoma.

    Science.gov (United States)

    Sanmartín, Elena; Yáñez, Yania; Fornés-Ferrer, Victoria; Zugaza, José L; Cañete, Adela; Castel, Victoria; Font de Mora, Jaime

    2017-07-11

    Identification of tumor driver mutations is crucial for improving clinical outcome using a personalized approach to the treatment of cancer. Neuroblastoma is a tumor of the peripheral sympathetic nervous system for which only a few driver alterations have been described including MYCN amplification and ALK mutations. We assessed 106 primary neuroblastoma tumors by next generation sequencing using a customized amplicon-based gene panel. Our results reveal that genetic variants in TIAM1 gene associate with better clinical outcome, suggesting a role for these TIAM1 variants in preventing progression of this disease. The detected variants are located within the different domains of TIAM1 that signal to the upstream regulator RAS and downstream effector molecules MYC and RAC, which are all implicated in neuroblastoma etiology and progression. Clinical outcome was improved in tumors where a TIAM1 variant was present concomitantly with either ALK mutation or MYCN amplification. Given the function of these signaling molecules in cell survival, proliferation, differentiation and neurite outgrowth, our data suggest that the TIAM1-mediated network is essential to neuroblastoma and thus, inhibiting TIAM1 reflects a rational strategy for improving therapy efficacy in neuroblastoma.

  1. Quantitative Missense Variant Effect Prediction Using Large-Scale Mutagenesis Data.

    Science.gov (United States)

    Gray, Vanessa E; Hause, Ronald J; Luebeck, Jens; Shendure, Jay; Fowler, Douglas M

    2018-01-24

    Large datasets describing the quantitative effects of mutations on protein function are becoming increasingly available. Here, we leverage these datasets to develop Envision, which predicts the magnitude of a missense variant's molecular effect. Envision combines 21,026 variant effect measurements from nine large-scale experimental mutagenesis datasets, a hitherto untapped training resource, with a supervised, stochastic gradient boosting learning algorithm. Envision outperforms other missense variant effect predictors both on large-scale mutagenesis data and on an independent test dataset comprising 2,312 TP53 variants whose effects were measured using a low-throughput approach. This dataset was never used for hyperparameter tuning or model training and thus serves as an independent validation set. Envision prediction accuracy is also more consistent across amino acids than other predictors. Finally, we demonstrate that Envision's performance improves as more large-scale mutagenesis data are incorporated. We precompute Envision predictions for every possible single amino acid variant in human, mouse, frog, zebrafish, fruit fly, worm, and yeast proteomes (https://envision.gs.washington.edu/). Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Leapfrog variants of iterative methods for linear algebra equations

    Science.gov (United States)

    Saylor, Paul E.

    1988-01-01

    Two iterative methods are considered, Richardson's method and a general second order method. For both methods, a variant of the method is derived for which only even numbered iterates are computed. The variant is called a leapfrog method. Comparisons between the conventional form of the methods and the leapfrog form are made under the assumption that the number of unknowns is large. In the case of Richardson's method, it is possible to express the final iterate in terms of only the initial approximation, a variant of the iteration called the grand-leap method. In the case of the grand-leap variant, a set of parameters is required. An algorithm is presented to compute these parameters that is related to algorithms to compute the weights and abscissas for Gaussian quadrature. General algorithms to implement the leapfrog and grand-leap methods are presented. Algorithms for the important special case of the Chebyshev method are also given.

  3. Characterization of Canine parvovirus 2 variants circulating in Greece.

    Science.gov (United States)

    Ntafis, Vasileios; Xylouri, Eftychia; Kalli, Iris; Desario, Costantina; Mari, Viviana; Decaro, Nicola; Buonavoglia, Canio

    2010-09-01

    The aim of the present study was to characterize Canine parvovirus 2 (CPV-2) variants currently circulating in Greece. Between March 2008 and March 2009, 167 fecal samples were collected from diarrheic dogs from different regions of Greece. Canine parvovirus 2 was detected by standard polymerase chain reaction, whereas minor groove binder probe assays were used to distinguish genetic variants and discriminate between vaccine and field strains. Of 84 CPV-2-positive samples, 81 CPV-2a, 1 CPV-2b, and 2 CPV-2c were detected. Vaccine strains were not detected in any sample. Sequence analysis of the VP2 gene of the 2 CPV-2c viruses revealed up to 100% amino acid identity with the CPV-2c strains previously detected in Europe. The results indicated that, unlike other European countries, CPV-2a remains the most common variant in Greece, and that the CPV-2c variant found in Europe is also present in Greece.

  4. wANNOVAR: annotating genetic variants for personal genomes via the web.

    Science.gov (United States)

    Chang, Xiao; Wang, Kai

    2012-07-01

    High-throughput DNA sequencing platforms have become widely available. As a result, personal genomes are increasingly being sequenced in research and clinical settings. However, the resulting massive amounts of variants data pose significant challenges to the average biologists and clinicians without bioinformatics skills. We developed a web server called wANNOVAR to address the critical needs for functional annotation of genetic variants from personal genomes. The server provides simple and intuitive interface to help users determine the functional significance of variants. These include annotating single nucleotide variants and insertions/deletions for their effects on genes, reporting their conservation levels (such as PhyloP and GERP++ scores), calculating their predicted functional importance scores (such as SIFT and PolyPhen scores), retrieving allele frequencies in public databases (such as the 1000 Genomes Project and NHLBI-ESP 5400 exomes), and implementing a 'variants reduction' protocol to identify a subset of potentially deleterious variants/genes. We illustrated how wANNOVAR can help draw biological insights from sequencing data, by analysing genetic variants generated on two Mendelian diseases. We conclude that wANNOVAR will help biologists and clinicians take advantage of the personal genome information to expedite scientific discoveries. The wANNOVAR server is available at http://wannovar.usc.edu, and will be continuously updated to reflect the latest annotation information.

  5. Differences in antimicrobial susceptibility of pigmented and unpigmented colonial variants of Mycobacterium avium.

    Science.gov (United States)

    Stormer, R S; Falkinham, J O

    1989-01-01

    Unpigmented colonial variants were isolated from pigmented Mycobacterium avium isolates recovered from patients with acquired immunodeficiency syndrome and the environment. The variants were interconvertible: the rate of transition from unpigmented to pigmented type was 4.0 x 10(-5) variants per cell per generation. The unpigmented variants were more tolerant to antibiotics, especially beta-lactams, and Cd2+ and Cu2+ salts than were their pigmented parents. Both pigmented and unpigmented variants of the strains produced beta-lactamase, although beta-lactamase did not appear to be a determinant of beta-lactam susceptibility. Pigmented variants grew more rapidly in a number of commonly used mycobacterial media, were more hydrophobic, and had higher carotenoid contents than their unpigmented segregants. PMID:2808669

  6. Identification of POMC exonic variants associated with substance dependence and body mass index.

    Directory of Open Access Journals (Sweden)

    Fan Wang

    Full Text Available Risk of substance dependence (SD and obesity has been linked to the function of melanocortin peptides encoded by the proopiomelanocortin gene (POMC.POMC exons were Sanger sequenced in 280 African Americans (AAs and 308 European Americans (EAs. Among them, 311 (167 AAs and 114 EAs were affected with substance (alcohol, cocaine, opioid and/or marijuana dependence and 277 (113 AAs and164 EAs were screened controls. We identified 23 variants, including two common polymorphisms (rs10654394 and rs1042571 and 21 rare variants; 12 of which were novel. We used logistic regression to analyze the association between the two common variants and SD or body mass index (BMI, with sex, age, and ancestry proportion as covariates. The common variant rs1042571 in the 3'UTR was significantly associated with BMI in EAs (Overweight: P(adj = 0.005; Obese: P(adj = 0.018; Overweight+Obese: P(adj = 0.002 but not in AAs. The common variant, rs10654394, was not associated with BMI and neither common variant was associated with SD in either population. To evaluate the association between the rare variants and SD or BMI, we collapsed rare variants and tested their prevalence using Fisher's exact test. In AAs, rare variants were nominally associated with SD overall and with specific SD traits (SD: P(FET,1df = 0.026; alcohol dependence: P(FET,1df = 0.027; cocaine dependence: P(FET,1df = 0.007; marijuana dependence: P(FET,1df = 0.050 (the P-value from cocaine dependence analysis survived Bonferroni correction. There was no such effect in EAs. Although the frequency of the rare variants did not differ significantly between the normal-weight group and the overweight or obese group in either population, certain rare exonic variants occurred only in overweight or obese subjects without SD.These findings suggest that POMC exonic variants may influence risk for both SD and elevated BMI, in a population-specific manner. However, common and rare variants in this gene may exert

  7. Clinical spectrum of KIAA2022 pathogenic variants in males: Case report of two boys with kiaa2022 pathogenic variants and review of the literature.

    Science.gov (United States)

    Lorenzo, Melissa; Stolte-Dijkstra, Irene; van Rheenen, Patrick; Smith, Ronald Garth; Scheers, Tom; Walia, Jagdeep S

    2018-04-25

    KIAA2022 is an X-linked intellectual disability (XLID) syndrome affecting males more severely than females. Few males with KIAA2022 variants and XLID have been reported. We present a clinical report of two unrelated males, with two nonsense KIAA2022 pathogenic variants, with profound intellectual disabilities, limited language development, strikingly similar autistic behavior, delay in motor milestones, and postnatal growth restriction. Patient 1, 19-years-old, has long ears, deeply set eyes with keratoconus, strabismus, a narrow forehead, anteverted nares, café-au-lait spots, macroglossia, thick vermilion of the upper and lower lips, and prognathism. He has gastroesophageal reflux, constipation with delayed rectosigmoid colonic transit time, difficulty regulating temperature, several musculoskeletal issues, and a history of one grand mal seizure. Patient 2, 10-years-old, has mild dysmorphic features, therapy resistant vomiting with diminished motility of the stomach, mild constipation, cortical visual impairment with intermittent strabismus, axial hypotonia, difficulty regulating temperature, and cutaneous mastocytosis. Genetic testing identified KIAA2022 variant c.652C > T(p.Arg218*) in Patient 1, and a novel nonsense de novo variant c.2707G > T(p.Glu903*) in Patient 2. We also summarized features of all reported males with KIAA2022 variants to date. This report not only adds knowledge of a novel pathogenic variant to the KIAA2022 variant database, but also likely extends the spectrum by describing novel dysmorphic features and medical conditions including macroglossia, café-au-lait spots, keratoconus, severe cutaneous mastocytosis, and motility problems of the GI tract, which may help physicians involved in the care of patients with this syndrome. Lastly, we describe the power of social media in bringing families with rare medical conditions together. © 2018 Wiley Periodicals, Inc.

  8. Cerivastatin, Genetic Variants, and the Risk of Rhabdomyolysis

    Science.gov (United States)

    Marciante, Kristin D.; Durda, Jon P.; Heckbert, Susan R.; Lumley, Thomas; Rice, Ken; McKnight, Barbara; Totah, Rheem A.; Tamraz, Bani; Kroetz, Deanna L.; Fukushima, Hisayo; Kaspera, Rüdiger; Bis, Joshua C.; Glazer, Nicole L.; Li, Guo; Austin, Thomas R.; Taylor, Kent D.; Rotter, Jerome I.; Jaquish, Cashell E.; Kwok, Pui-Yan; Tracy, Russell P.; Psaty, Bruce M.

    2011-01-01

    Objective The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response--rhabdomyolysis in a small proportion of users-- points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis. Methods The study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association (GWA) study to identify risk factors in other regions of the genome. 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies. Results Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (p = 0.002), but not variants in CYP2C8 (p = 0.073) or the UGTs (p = 0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (OR: 1.89, 95% CI: 1.40 to 2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (p rhabdomyolysis (OR: 0.48; 95% CI: 0.36 to 0.63). Conclusion We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin. PMID:21386754

  9. Identification of Inherited Retinal Disease-Associated Genetic Variants in 11 Candidate Genes.

    Science.gov (United States)

    Astuti, Galuh D N; van den Born, L Ingeborgh; Khan, M Imran; Hamel, Christian P; Bocquet, Béatrice; Manes, Gaël; Quinodoz, Mathieu; Ali, Manir; Toomes, Carmel; McKibbin, Martin; El-Asrag, Mohammed E; Haer-Wigman, Lonneke; Inglehearn, Chris F; Black, Graeme C M; Hoyng, Carel B; Cremers, Frans P M; Roosing, Susanne

    2018-01-10

    Inherited retinal diseases (IRDs) display an enormous genetic heterogeneity. Whole exome sequencing (WES) recently identified genes that were mutated in a small proportion of IRD cases. Consequently, finding a second case or family carrying pathogenic variants in the same candidate gene often is challenging. In this study, we searched for novel candidate IRD gene-associated variants in isolated IRD families, assessed their causality, and searched for novel genotype-phenotype correlations. Whole exome sequencing was performed in 11 probands affected with IRDs. Homozygosity mapping data was available for five cases. Variants with minor allele frequencies ≤ 0.5% in public databases were selected as candidate disease-causing variants. These variants were ranked based on their: (a) presence in a gene that was previously implicated in IRD; (b) minor allele frequency in the Exome Aggregation Consortium database (ExAC); (c) in silico pathogenicity assessment using the combined annotation dependent depletion (CADD) score; and (d) interaction of the corresponding protein with known IRD-associated proteins. Twelve unique variants were found in 11 different genes in 11 IRD probands. Novel autosomal recessive and dominant inheritance patterns were found for variants in Small Nuclear Ribonucleoprotein U5 Subunit 200 ( SNRNP200 ) and Zinc Finger Protein 513 ( ZNF513 ), respectively. Using our pathogenicity assessment, a variant in DEAH-Box Helicase 32 ( DHX32 ) was the top ranked novel candidate gene to be associated with IRDs, followed by eight medium and lower ranked candidate genes. The identification of candidate disease-associated sequence variants in 11 single families underscores the notion that the previously identified IRD-associated genes collectively carry > 90% of the defects implicated in IRDs. To identify multiple patients or families with variants in the same gene and thereby provide extra proof for pathogenicity, worldwide data sharing is needed.

  10. Integrating functional data to prioritize causal variants in statistical fine-mapping studies.

    Directory of Open Access Journals (Sweden)

    Gleb Kichaev

    2014-10-01

    Full Text Available Standard statistical approaches for prioritization of variants for functional testing in fine-mapping studies either use marginal association statistics or estimate posterior probabilities for variants to be causal under simplifying assumptions. Here, we present a probabilistic framework that integrates association strength with functional genomic annotation data to improve accuracy in selecting plausible causal variants for functional validation. A key feature of our approach is that it empirically estimates the contribution of each functional annotation to the trait of interest directly from summary association statistics while allowing for multiple causal variants at any risk locus. We devise efficient algorithms that estimate the parameters of our model across all risk loci to further increase performance. Using simulations starting from the 1000 Genomes data, we find that our framework consistently outperforms the current state-of-the-art fine-mapping methods, reducing the number of variants that need to be selected to capture 90% of the causal variants from an average of 13.3 to 10.4 SNPs per locus (as compared to the next-best performing strategy. Furthermore, we introduce a cost-to-benefit optimization framework for determining the number of variants to be followed up in functional assays and assess its performance using real and simulation data. We validate our findings using a large scale meta-analysis of four blood lipids traits and find that the relative probability for causality is increased for variants in exons and transcription start sites and decreased in repressed genomic regions at the risk loci of these traits. Using these highly predictive, trait-specific functional annotations, we estimate causality probabilities across all traits and variants, reducing the size of the 90% confidence set from an average of 17.5 to 13.5 variants per locus in this data.

  11. ADULT VARIANT BARTTER’S SYNDROME- A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Ishwar Sidappa Hasabi

    2017-02-01

    Full Text Available BACKGROUND Bartter syndrome is a group of channelopathies with different genetic origins and molecular pathophysiologies, but sharing common feature of decreased tubular transport of sodium chloride in thick ascending loop of Henle (TAL, 1 although more common in antenatal group. Classic adult variant of Bartter syndrome is a rare entity. We hereby present a rare adult variant of classic Bartter syndrome.

  12. HABP2 G534E Variant in Papillary Thyroid Carcinoma.

    Directory of Open Access Journals (Sweden)

    Jerneja Tomsic

    Full Text Available The main nonmedullary form of thyroid cancer is papillary thyroid carcinoma (PTC that accounts for 80-90% of all thyroid malignancies. Only 3-10% of PTC patients have a positive family history of PTC yet the familiality is one of the highest of all cancers as measured by case control studies. A handful of genes have been implicated accounting for a small fraction of this genetic predisposition. It was therefore of considerable interest that a mutation in the HABP2 gene was recently implicated in familial PTC. The present work was undertaken to examine the extent of HABP2 variant involvement in PTC. The HABP2 G534E variant (rs7080536 was genotyped in blood DNA from 179 PTC families (one affected individual per family, 1160 sporadic PTC cases and 1395 controls. RNA expression of HABP2 was tested by qPCR in RNA extracted from tumor and normal thyroid tissue from individuals that are homozygous wild-type or heterozygous for the variant. The variant was found to be present in 6.1% familial cases, 8.0% sporadic cases (2 individuals were homozygous for the variant and 8.7% controls. The variant did not segregate with PTC in one large and 6 smaller families in which it occurred. In keeping with data from the literature and databases the expression of HABP2 was highest in the liver, much lower in 3 other tested tissues (breast, kidney, brain but not found in thyroid. Given these results showing lack of any involvement we suggest that the putative role of variant HABP2 in PTC should be carefully scrutinized.

  13. Genotyping Fanconi anemia patients from Serbia reveals three novel FANCD2 variants

    Directory of Open Access Journals (Sweden)

    Filipović-Tričković Jelena

    2017-01-01

    Full Text Available Fanconi anemia is rare inherited disease characterized by wide spectrum of congenital anomalies, progressive pancytopenia, and predisposition to hematological malignancies and solid tumors. Molecular genetic analysis of mutations in FANC genes is of a great importance for diagnosis confirmation, prenatal and carrier testing, as well as for prediction of chemotherapy outcome and disease complications. In this study we performed screening of frequently affected regions of FANCD2 gene for sequence variants in six unrelated FA-D2 patients in Serbia. This is the first molecular analysis of FANCD2 gene in Serbian FA-D2 patients. A total of 10 sequence variants were detected, one in homozygous, and nine in heterozygous state. Two variants were found within exons, and eight within introns, in deep intronic regions. In-silico analysis showed that among all detected variants one exon variant and three intron variants might have impact on splicing mechanism. Heterozygous variants found in intron 3, c.206-246delG; exon 26, c.2396 C>A and intron 28, c.2715+573 C>T were not previously reported. In-silico analysis revealed that among them, two (intron 3, c.206-246 delG and exon 26, c.2396 C>A could be novel disease-causing mutations. Many variants were found in more than one patient, including those unreported, indicating their possible ethnic association. Great number of variants in some patients suggests their non-random emergence in Fanconi anemia pathway. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 173046

  14. Androgen Receptor Splice Variants and Resistance to Taxane Chemotherapy

    Science.gov (United States)

    2017-10-01

    resistant prostate cancer ; docetaxel; cabazitaxel; chemotherapy; androgen receptor splice variants; microtubule; ligand-binding domain; microtubule... receptor splice variants (AR-Vs) are associated with resistance to taxane chemotherapy in castration- resistant prostate cancer (CRPC). However, this...androgen receptor inhibitors in prostate cancer . Nat Rev Cancer . 2015;15:701–11.

  15. PET/TAC: Basic principles, physiological variants and artifacts; PET/TAC: Generalidades, variantes fisiologicas y artefactos

    Energy Technology Data Exchange (ETDEWEB)

    Jimenez V, A.M. [Especialista en Medicina Nuclear, Profa. Depto. Radiologia de la Facultad de Medicina, Universidad Complutense de Madrid, Madrid (Spain)

    2007-07-01

    This presentation is about the basic principles, physiologic variants and devices that work in the PET/TAC technique. Next the conclusions obtained in the same one are presented: For a correct evaluation of the PET/TAC images with FDG is necessary the knowledge of the image acquisition technique, as well as of the physiologic distribution of the FDG, variants of the normality, benign causes of captation and more frequent devices. The introduction of this hybrid procedure allows the correct anatomical localization and identification of the deposits of FDG largely avoiding false or doubtful interpretations, but it can also originate not specific devices existent in the conventional PET. The previous knowledge of the possible devices will make possible in certain cases its elimination and in other its identification avoiding incorrect interpretations. (Author)

  16. Structure of chymotrypsin variant B from Atlantic cod, Gadus morhua

    DEFF Research Database (Denmark)

    Leth-Larsen, Rikke; Asgeirsson, B; Thórólfsson, M

    1996-01-01

    The amino-acid sequence of chymotrypsin variant B isolated from the pyloric caeca of Atlantic cod has been elucidated. The characterization of the primary structure is based on N-terminal Edman degradation and mass spectrometry of the native protein and enzymatically derived peptides. Chymotrypsi...... autolysis sites, cod variant B only contains a single autolysis site. The three-dimensional structures of the A- and B-variants of cod has been modelled on the known crystal structure of bovine alpha-chymotrypsin showing almost superimposable structures....

  17. Rare novel variants in the ZIC3 gene cause X-linked heterotaxy

    DEFF Research Database (Denmark)

    Paulussen, Aimee D C; Steyls, Anja; Vanoevelen, Jo

    2016-01-01

    male deaths due to heterotaxy in the family (n=1). All variants were located within the zinc-finger domains or leading to a truncation before these domains. Truncating variants showed abnormal trafficking of mutated ZIC3 proteins, whereas the missense variant showed normal trafficking. Overexpression...

  18. Rare human papillomavirus 16 E6 variants reveal significant oncogenic potential

    Directory of Open Access Journals (Sweden)

    Tommasino Massimo

    2011-06-01

    Full Text Available Abstract The aim of this study was to determine whether low prevalence human papillomavirus (HPV 16 E6 variants differ from high prevalence types in their functional abilities. We evaluated functions relevant to carcinogenesis for the rarely-detected European variants R8Q, R10G and R48W as compared to the commonly detected L83V. Human immortalized keratinocytes (NIKS stably transduced with the E6 variants were used in most functional assays. Low and high prevalence E6 variants displayed similar abilities in abrogation of growth arrest and inhibition of p53 elevation induced by actinomycin D. Differences were detected in the abilities to dysregulate stratification and differentiation of NIKS in organotypic raft cultures, modulate detachment induced apoptosis (anoikis and hyperactivate Wnt signaling. No distinctive phenotype could be assigned to include all rare variants. Like L83V, raft cultures derived from variants R10G and R48W similarly induced hyperplasia and aberrantly expressed keratin 5 in the suprabasal compartment with significantly lower expression of keratin 10. Unlike L83V, both variants, and particularly R48W, induced increased levels of anoikis upon suspension in semisolid medium. R8Q induced a unique phenotype characterized by thin organotypic raft cultures, low expression of keratin 10, and high expression of keratins 5 and 14 throughout all raft layers. Interestingly, in a reporter based assay R8Q exhibited a higher ability to augment TCF/β-catenin transcription. The data suggests that differences in E6 variant prevalence in cervical carcinoma may not be related to the carcinogenic potential of the E6 protein.

  19. Genomewide association study identifies no major founder variant in ...

    Indian Academy of Sciences (India)

    2013-12-10

    Dec 10, 2013 ... variant in Caucasian moyamoya disease ... 1Department of Health and Environmental Sciences, Kyoto University Graduate ... a low prevalence in European countries (Goto and Yonekawa. 1992; Kuroda and Houkin 2008). We have found that the p.R4810K variant in the ring finger protein 213 (RNF213).

  20. Screening for common copy-number variants in cancer genes.

    Science.gov (United States)

    Tyson, Jess; Majerus, Tamsin M O; Walker, Susan; Armour, John A L

    2010-12-01

    For most cases of colorectal cancer that arise without a family history of the disease, it is proposed that an appreciable heritable component of predisposition is the result of contributions from many loci. Although progress has been made in identifying single nucleotide variants associated with colorectal cancer risk, the involvement of low-penetrance copy number variants is relatively unexplored. We have used multiplex amplifiable probe hybridization (MAPH) in a fourfold multiplex (QuadMAPH), positioned at an average resolution of one probe per 2 kb, to screen a total of 1.56 Mb of genomic DNA for copy number variants around the genes APC, AXIN1, BRCA1, BRCA2, CTNNB1, HRAS, MLH1, MSH2, and TP53. Two deletion events were detected, one upstream of MLH1 in a control individual and the other in APC in a colorectal cancer patient, but these do not seem to correspond to copy number polymorphisms with measurably high population frequencies. In summary, by means of our QuadMAPH assay, copy number measurement data were of sufficient resolution and accuracy to detect any copy number variants with high probability. However, this study has demonstrated a very low incidence of deletion and duplication variants within intronic and flanking regions of these nine genes, in both control individuals and colorectal cancer patients. Copyright © 2010 Elsevier Inc. All rights reserved.

  1. Coronary artery anatomy and variants

    Energy Technology Data Exchange (ETDEWEB)

    Malago, Roberto; Pezzato, Andrea; Barbiani, Camilla; Alfonsi, Ugolino; Nicoli, Lisa; Caliari, Giuliana; Pozzi Mucelli, Roberto [Policlinico G.B. Rossi, University of Verona, Department of Radiology, Verona (Italy)

    2011-12-15

    Variants and congenital anomalies of the coronary arteries are usually asymptomatic, but may present with severe chest pain or cardiac arrest. The introduction of multidetector CT coronary angiography (MDCT-CA) allows the detection of significant coronary artery stenosis. Improved performance with isotropic spatial resolution and higher temporal resolution provides a valid alternative to conventional coronary angiography (CCA) in many patients. MDCT-CA is now considered the ideal tool for three-dimensional visualization of the complex and tortuous anatomy of the coronary arteries. With multiplanar and volume-rendered reconstructions, MDCT-CA may even outperform CCA in determining the relative position of vessels, thus providing a better view of the coronary vascular anatomy. The purpose of this review is to describe the normal anatomy of the coronary arteries and their main variants based on MDCT-CA with appropriate reconstructions. (orig.)

  2. GBA Variants Influence Motor and Non-Motor Features of Parkinson’s Disease

    Science.gov (United States)

    Jesús, Silvia; Huertas, Ismael; Cáceres-Redondo, María Teresa; Vargas-González, Laura; Gómez-Llamas, Myriam; Carrillo, Fátima; Calderón, Enrique; Carballo, Manuel; Gómez-Garre, Pilar; Mir, Pablo

    2016-01-01

    The presence of mutations in glucocerebrosidase (GBA) gene is a known factor increasing the risk of developing Parkinson’s disease (PD). Mutations carriers have earlier disease onset and are more likely to develop neuropsychiatric symptoms than other sporadic PD cases. These symptoms have primarily been observed in Parkinson’s patients carrying the most common pathogenic mutations L444P and N370S. However, recent findings suggest that other variants across the gene may have a different impact on the phenotype as well as on the disease progression. We aimed to explore the influence of variants across GBA gene on the clinical features and treatment related complications in PD. In this study, we screened the GBA gene in a cohort of 532 well-characterised PD patients and 542 controls from southern Spain. The potential pathogeniticy of the identified variants was assessed using in-silico analysis and subsequently classified as benign or deleterious. As a result, we observed a higher frequency of GBA variants in PD patients (12.2% vs. 7.9% in controls, p = 0.021), earlier mean age at disease onset in GBA variant carriers (50.6 vs. 56.6 years; p = 0.013), as well as more prevalent motor and non-motor symptoms in patients carrying deleterious variants. In addition, we found that dopaminergic motor complications are influenced by both benign and deleterious variants. Our results highlight the fact that the impact on the phenotype highly depends on the potential pathogenicity of the carried variants. Therefore, the course of motor and non-motor symptoms as well as treatment-related motor complications could be influenced by GBA variants. PMID:28030538

  3. Simple and complex dysembryoplastic neuroepithelial tumors (DNT) variants: clinical profile, MRI, and histopathology

    Energy Technology Data Exchange (ETDEWEB)

    Campos, Alexandre R.; Clusmann, Hans; Lehe, Marec von; Schramm, Johannes [University of Bonn Medical Center, Department of Neurosurgery, Bonn (Germany); Niehusmann, Pitt; Becker, Albert J. [University of Bonn Medical Center, Department of Neuropathology, Bonn (Germany); Urbach, Horst [University of Bonn Medical Center, Department of Radiology, Bonn (Germany)

    2009-07-15

    Dysembryoplastic neuroepithelial tumors (DNTs) are long-term epilepsy associated tumors subdivided into simple and complex variants. The purpose of this study was to relate different DNT components identified on magnetic resonance imaging (MRI) to histopathological features and to test the hypothesis that glial nodules as a histopathological feature of complex variants induce an occasional glioma misdiagnosis. Clinical, MRI, and histopathologic features of DNTs operated between 1988 and 2008 were reviewed. From a total of 61 DNTs, 48 simple and 13 complex variants were identified. Multiple or single pseudocysts in a cortical/subcortical location with small cysts sometimes separated from the tumor represented the glioneuronal element and were found in all DNTs. FLAIR hyperintense tissue was found between pseudocysts but - in neocortical DNTs - also circumscript in deeper tumor parts. Calcification and hemorrhages in this location occurred in four of 13 complex variants, and one of these patients was also the only one with tumor growth. Patients with complex variants had earlier seizure onset, and complex variants were more often located outside the temporal lobe. Although complex variants represented a higher diagnostic challenge, misdiagnoses also occurred in simple variants. One of five of DNTs showed contrast enhancement, which varied on follow-up studies with enhancing parts becoming nonenhancing and vice versa. The glioneuronal element is readily identifiable on MRI and should be considered to support the DNT diagnosis. Complex DNT variants have a different clinical profile and a more variable histopathological and MRI appearance; however, misdiagnoses occasionally also occur in simple variants. (orig.)

  4. Analysis of mtDNA sequence variants in colorectal adenomatous polyps

    Directory of Open Access Journals (Sweden)

    Grizzle William

    2010-10-01

    Full Text Available Abstract Colorectal tumors mostly arise from sporadic adenomatous polyps. Polyps are defined as a mass of cells that protrudes into the lumen of the colon. Adenomatous polyps are benign neoplasms that, by definition display some characteristics of dysplasia. It has been shown that polyps were benign tumors which may undergo malignant transformation. Adenomatous polyps have been classified into three histologic types; tubular, tubulovillous, and villous with increasing malignant potential. The ability to differentially diagnose these colorectal adenomatous polyps is important for therapeutic intervention. To date, little efforts have been directed to identifying genetic changes involved in adenomatous polyps. This study was designed to examine the relevance of mitochondrial genome alterations in the three adenomatous polyps. Using high resolution restriction endonucleases and PCR-based sequencing, fifty-seven primary fresh frozen tissues of adenomatous polyps (37 tumors and 20 matched surrounding normal tissues obtained from the southern regional Cooperative Human Tissue Network (CHTN and Grady Memorial Hospital at Atlanta were screened with three mtDNA regional primer pairs that spanned 5.9 kbp. Results from our data analyses revealed the presence of forty-four variants in some of these mitochondrial genes that the primers spanned; COX I, II, III, ATP 6, 8, CYT b, ND 5, 6 and tRNAs. Based on the MITODAT database as a sequence reference, 25 of the 44 (57% variants observed were unreported. Notably, a heteroplasmic variant C8515G/T in the MT-ATP 8 gene and a germline variant 8327delA in the tRNAlys was observed in all the tissue samples of the three adenomatous polyps in comparison to the referenced database sequence. A germline variant G9055A in the MT-ATP 6 gene had a frequency of 100% (17/17 in tubular and 57% (13/23 in villous adenomas; no corresponding variant was in tubulovillous adenomas. Furthermore, A9006G variant at MT-ATP 6 gene was

  5. The characteristics of transferrin variants by carbohydrate-deficient transferrin tests using capillary zone electrophoresis.

    Science.gov (United States)

    Yoo, Gilsung; Kim, Juwon; Yoon, Kap Joon; Lee, Jong-Han

    2018-04-17

    Transferrin is the major plasma transport protein for iron. We aimed to investigate the characteristics of transferrin variant by carbohydrate-deficient transferrin (CDT) test using capillary zone electrophoresis. We retrospectively analyzed the CDT tests of 2449 patients from March 2009 to May 2017 at a tertiary hospital in Korea. CDT was quantified using a Capillarys 2 system (Sebia, Lisses, France) by capillary zone electrophoresis. The characteristics of variant transferrin patterns using electropherogram of CDT tests were analyzed. Seventy-seven (3.1%) patients were classified as variant transferrin. Mean age of these patients was 51.8 years, and the male-to-female ratio was 3.5:1. The most common variants were the BC variants (n = 37), followed by the CD variants (n = 27), unclear patterns (n = 7), BD variants (n = 3), CC variants (n = 2), misclassification (n = 1). In the variant Tf group, the most common disease was alcoholic liver cirrhosis (n = 22, 28.6%), followed by the toxic effects of substances (n = 17, 22.1%), and mental and behavioral disorders attributable to alcohol (n = 11, 14.3%). Nonvariant group showed a predominance of the toxic substance effects (n = 880, 37.1%), a personal history of suicide attempts (n = 634, 26.7%), and mental and behavioral disorders due to alcohol (n = 336, 14.2%). We analyzed the basic characteristics of variant transferrin by CDT tests using capillary zone electrophoresis. The prevalence of variant transferrin was 3.1% of the study subjects. Male patients, alcohol abusers, and liver cirrhosis patients predominated in the variant transferrin population. Further prospective studies are warranted to elucidate variant transferrin in clinical practice. © 2018 Wiley Periodicals, Inc.

  6. Human papillomavirus type 16 molecular variants in Guarani Indian women from Misiones, Argentina.

    Science.gov (United States)

    Tonon, Sergio Andrés; Basiletti, Jorge; Badano, Ines; Alonio, Lidia Virginia; Villa, Luisa Lina; Teyssie, Angélica Rita; Picconi, María Alejandra

    2007-01-01

    To identify human papillomavirus type 16 (HPV16) E6 and L1 molecular variants infecting Guarani Indian women settled in Misiones, Argentina, a region with a high prevalence of cervical cancer. Some intratypic molecular variants of HPV16 have been associated with greater oncogenic risk, but their implication in the etiology of cervical cancer is still uncertain. Seventy HPV16 positive cervical samples from Guarani Indian women settled in two different areas of Misiones, Argentina, (34 from the northern area and 36 from the central area), were analyzed. Thirty-seven had normal cytology, 18 had a low-grade squamous intraepithelial lesion (LGSIL), and 15 a high-grade squamous intraepithelial lesion (HGSIL). HPV16 E6 and L1 molecular variants were identified by PCR, followed by dot blot hybridization with 23 and 12 biotinylated oligonucleotide probes, respectively. The frequency of HPV16 variants over the Guarani population was 51% EP (European prototype), 32% E-350G, 9% Af1-a (African 1), 4% E-6862C, 3% Af2-a, and 1% AA-a (Asian-American). The distribution of variants was not homogeneous in the two areas under analysis, with the northern area being more diverse showing 74% of European variants, while the central area presented exclusively E variants. No statistically significant association was found between any particular variant and grade of cervical lesion. This study reports for the first time HPV16 E6 and L1 molecular variants infecting women from an aboriginal community inhabiting a rainforest region of South America. The presence of E class variants could be attributed primarily to contacts with the Spanish conquerors, and Af variants from African slaves introduced later in the South American continent.

  7. Functionally significant, rare transcription factor variants in tetralogy of Fallot.

    Directory of Open Access Journals (Sweden)

    Ana Töpf

    Full Text Available Rare variants in certain transcription factors involved in cardiac development cause Mendelian forms of congenital heart disease. The purpose of this study was to systematically assess the frequency of rare transcription factor variants in sporadic patients with the cardiac outflow tract malformation tetralogy of Fallot (TOF.We sequenced the coding, 5'UTR, and 3'UTR regions of twelve transcription factor genes implicated in cardiac outflow tract development (NKX2.5, GATA4, ISL1, TBX20, MEF2C, BOP/SMYD1, HAND2, FOXC1, FOXC2, FOXH, FOXA2 and TBX1 in 93 non-syndromic, non-Mendelian TOF cases. We also analysed Illumina Human 660W-Quad SNP Array data for copy number variants in these genes; none were detected. Four of the rare variants detected have previously been shown to affect transactivation in in vitro reporter assays: FOXC1 p.P297S, FOXC2 p.Q444R, FOXH1 p.S113T and TBX1 p.P43_G61del PPPPRYDPCAAAAPGAPGP. Two further rare variants, HAND2 p.A25_A26insAA and FOXC1 p.G378_G380delGGG, A488_491delAAAA, affected transactivation in in vitro reporter assays. Each of these six functionally significant variants was present in a single patient in the heterozygous state; each of the four for which parental samples were available were maternally inherited. Thus in the 93 TOF cases we identified six functionally significant mutations in the secondary heart field transcriptional network.This study indicates that rare genetic variants in the secondary heart field transcriptional network with functional effects on protein function occur in 3-13% of patients with TOF. This is the first report of a functionally significant HAND2 mutation in a patient with congenital heart disease.

  8. OVAS: an open-source variant analysis suite with inheritance modelling.

    Science.gov (United States)

    Mozere, Monika; Tekman, Mehmet; Kari, Jameela; Bockenhauer, Detlef; Kleta, Robert; Stanescu, Horia

    2018-02-08

    The advent of modern high-throughput genetics continually broadens the gap between the rising volume of sequencing data, and the tools required to process them. The need to pinpoint a small subset of functionally important variants has now shifted towards identifying the critical differences between normal variants and disease-causing ones. The ever-increasing reliance on cloud-based services for sequence analysis and the non-transparent methods they utilize has prompted the need for more in-situ services that can provide a safer and more accessible environment to process patient data, especially in circumstances where continuous internet usage is limited. To address these issues, we herein propose our standalone Open-source Variant Analysis Sequencing (OVAS) pipeline; consisting of three key stages of processing that pertain to the separate modes of annotation, filtering, and interpretation. Core annotation performs variant-mapping to gene-isoforms at the exon/intron level, append functional data pertaining the type of variant mutation, and determine hetero/homozygosity. An extensive inheritance-modelling module in conjunction with 11 other filtering components can be used in sequence ranging from single quality control to multi-file penetrance model specifics such as X-linked recessive or mosaicism. Depending on the type of interpretation required, additional annotation is performed to identify organ specificity through gene expression and protein domains. In the course of this paper we analysed an autosomal recessive case study. OVAS made effective use of the filtering modules to recapitulate the results of the study by identifying the prescribed compound-heterozygous disease pattern from exome-capture sequence input samples. OVAS is an offline open-source modular-driven analysis environment designed to annotate and extract useful variants from Variant Call Format (VCF) files, and process them under an inheritance context through a top-down filtering schema of

  9. Biochemical characterization of the GM2 gangliosidosis B1 variant

    Directory of Open Access Journals (Sweden)

    Tutor J.C.

    2004-01-01

    Full Text Available The deficiency of the A isoenzyme of ß-hexosaminidase (Hex produced by different mutations of the gene that codes for the alpha subunit (Tay-Sachs disease has two variants with enzymological differences: the B variant consists of the absence of Hex A isoenzyme and the B1 variant produces an inactive Hex A isoenzyme for the hydrolysis of the GM2 ganglioside and synthetic substrates with negative charge. In contrast to the early childhood form of the B variant, the B1 variant appears at a later clinical stage (3 to 7 years of age with neurodegenerative symptoms leading to the death of the patient in the second decade of life. The most frequent mutation responsible for the GM2 gangliosidosis B1 variant is R178H, which has a widespread geographic and ethnic distribution. The highest incidence has been described in Portugal, which has been suggested as the point of origin of this mutation. Biochemical characterization of this lysosomal disease is carried out using negatively charged synthetic alpha subunit-specific sulfated substrates, since Hex A isoenzyme heat-inactivation assays are not applicable. However, the determination of the apparent activation energy of Hex using the neutral substrate 3,3'-dichlorophenolsulfonphthaleinyl N-acetyl-ß-D-glucosaminide, may offer a valid alternative. The presence of an alpha subunit in the alphaß heterodimer Hex A means that its activation energy (41.8 kJ/mol is significantly lower than that of the ßß homodimer Hex B (75.1 kJ/mol; however, as mutation inactivates the alpha subunit, the Hex A of the B1 variant presents an activation energy that is similar to that of the Hex B isoenzyme.

  10. HGVS Recommendations for the Description of Sequence Variants: 2016 Update.

    Science.gov (United States)

    den Dunnen, Johan T; Dalgleish, Raymond; Maglott, Donna R; Hart, Reece K; Greenblatt, Marc S; McGowan-Jordan, Jean; Roux, Anne-Francoise; Smith, Timothy; Antonarakis, Stylianos E; Taschner, Peter E M

    2016-06-01

    The consistent and unambiguous description of sequence variants is essential to report and exchange information on the analysis of a genome. In particular, DNA diagnostics critically depends on accurate and standardized description and sharing of the variants detected. The sequence variant nomenclature system proposed in 2000 by the Human Genome Variation Society has been widely adopted and has developed into an internationally accepted standard. The recommendations are currently commissioned through a Sequence Variant Description Working Group (SVD-WG) operating under the auspices of three international organizations: the Human Genome Variation Society (HGVS), the Human Variome Project (HVP), and the Human Genome Organization (HUGO). Requests for modifications and extensions go through the SVD-WG following a standard procedure including a community consultation step. Version numbers are assigned to the nomenclature system to allow users to specify the version used in their variant descriptions. Here, we present the current recommendations, HGVS version 15.11, and briefly summarize the changes that were made since the 2000 publication. Most focus has been on removing inconsistencies and tightening definitions allowing automatic data processing. An extensive version of the recommendations is available online, at http://www.HGVS.org/varnomen. © 2016 WILEY PERIODICALS, INC.

  11. Identifying pathogenicity of human variants via paralog-based yeast complementation.

    Directory of Open Access Journals (Sweden)

    Fan Yang

    2017-05-01

    Full Text Available To better understand the health implications of personal genomes, we now face a largely unmet challenge to identify functional variants within disease-associated genes. Functional variants can be identified by trans-species complementation, e.g., by failure to rescue a yeast strain bearing a mutation in an orthologous human gene. Although orthologous complementation assays are powerful predictors of pathogenic variation, they are available for only a few percent of human disease genes. Here we systematically examine the question of whether complementation assays based on paralogy relationships can expand the number of human disease genes with functional variant detection assays. We tested over 1,000 paralogous human-yeast gene pairs for complementation, yielding 34 complementation relationships, of which 33 (97% were novel. We found that paralog-based assays identified disease variants with success on par with that of orthology-based assays. Combining all homology-based assay results, we found that complementation can often identify pathogenic variants outside the homologous sequence region, presumably because of global effects on protein folding or stability. Within our search space, paralogy-based complementation more than doubled the number of human disease genes with a yeast-based complementation assay for disease variation.

  12. DSA analysis of the normal and variant hepatic arterial anatomy

    International Nuclear Information System (INIS)

    Lv Penghua; Wang Jie; Shi Haibing; Feng Yaoliang; Chen Huizhu; Chen Yuqin

    2005-01-01

    Objective: To observe and analyze the normal and variant hepatic arterial anatomy by DSA. Methods: One thousand and two hundreds patients with routine celiac and/or selective hepatic arteriography from November 1994 to March 2003 were retrospectively analyzed, some of them were further simultaneously undergone superior mesenteric arteriography, left gastric arteriography or inferior phrenic arteriography etc. Results: 873 (72.8%) patients had the standard hepatic arterial anatomy. 156(13.0%) patients had variant left hepatic arteries (LHAs), 120(10.0%) with variant right hepatic arteries (RHAs) and 21 (1.8%) of a variant anatomy involving both LHA and RHA. The common hepatic artery (CHA) of 1170 (97.5%) patients originated from the celiac artery. 92.0% proper hepatic artery (PHA) was the direct extension of CHA. The RHA was mainly (89.8%) derived from the PHA. There was some variation of the middle hepatic artery (MHA) with more than 62.2% arising from the LHA. The LHA was derived from the PHA (44.6%) or the RHA(30.2%) or other arteries (25.2%). Conclusions: The knowledge of normal and variant anatomy of hepatic vasculature by DSA may be very helpful for intervention therapy and hepatosurgery. (authors)

  13. RareVar: A Framework for Detecting Low-Frequency Single-Nucleotide Variants.

    Science.gov (United States)

    Hao, Yangyang; Xuei, Xiaoling; Li, Lang; Nakshatri, Harikrishna; Edenberg, Howard J; Liu, Yunlong

    2017-07-01

    Accurate identification of low-frequency somatic point mutations in tumor samples has important clinical utilities. Although high-throughput sequencing technology enables capturing such variants while sequencing primary tumor samples, our ability for accurate detection is compromised when the variant frequency is close to the sequencer error rate. Most current experimental and bioinformatic strategies target mutations with ≥5% allele frequency, which limits our ability to understand the cancer etiology and tumor evolution. We present an experimental and computational modeling framework, RareVar, to reliably identify low-frequency single-nucleotide variants from high-throughput sequencing data under standard experimental protocols. RareVar protocol includes a benchmark design by pooling DNAs from already sequenced individuals at various concentrations to target variants at desired frequencies, 0.5%-3% in our case. By applying a generalized, linear model-based, position-specific error model, followed by machine-learning-based variant calibration, our approach outperforms existing methods. Our method can be applied on most capture and sequencing platforms without modifying the experimental protocol.

  14. Antigen Loss Variants: Catching Hold of Escaping Foes.

    Science.gov (United States)

    Vyas, Maulik; Müller, Rolf; Pogge von Strandmann, Elke

    2017-01-01

    Since mid-1990s, the field of cancer immunotherapy has seen steady growth and selected immunotherapies are now a routine and preferred therapeutic option of certain malignancies. Both active and passive cancer immunotherapies exploit the fact that tumor cells express specific antigens on the cell surface, thereby mounting an immune response specifically against malignant cells. It is well established that cancer cells typically lose surface antigens following natural or therapy-induced selective pressure and these antigen-loss variants are often the population that causes therapy-resistant relapse. CD19 and CD20 antigen loss in acute lymphocytic leukemia and chronic lymphocytic leukemia, respectively, and lineage switching in leukemia associated with mixed lineage leukemia (MLL) gene rearrangements are well-documented evidences in this regard. Although increasing number of novel immunotherapies are being developed, majority of these do not address the control of antigen loss variants. Here, we review the occurrence of antigen loss variants in leukemia and discuss the therapeutic strategies to tackle the same. We also present an approach of dual-targeting immunoligand effectively retargeting NK cells against antigen loss variants in MLL-associated leukemia. Novel immunotherapies simultaneously targeting more than one tumor antigen certainly hold promise to completely eradicate tumor and prevent therapy-resistant relapses.

  15. Multiple Functional Variants in cis Modulate PDYN Expression.

    Science.gov (United States)

    Babbitt, Courtney C; Silverman, Jesse S; Haygood, Ralph; Reininga, Jennifer M; Rockman, Matthew V; Wray, Gregory A

    2010-02-01

    Understanding genetic variation and its functional consequences within cis-regulatory regions remains an important challenge in human genetics and evolution. Here, we present a fine-scale functional analysis of segregating variation within the cis-regulatory region of prodynorphin, a gene that encodes an endogenous opioid precursor with roles in cognition and disease. In order to characterize the functional consequences of segregating variation in cis in a region under balancing selection in different human populations, we examined associations between specific polymorphisms and gene expression in vivo and in vitro. We identified five polymorphisms within the 5' flanking region that affect transcript abundance: a 68-bp repeat recognized in prior studies, as well as two microsatellites and two single nucleotide polymorphisms not previously implicated as functional variants. The impact of these variants on transcription differs by brain region, sex, and cell type, implying interactions between cis genotype and the differentiated state of cells. The effects of individual variants on expression level are not additive in some combinations, implying epistatic interactions between nearby variants. These data reveal an unexpectedly complex relationship between segregating genetic variation and its expression-trait consequences and highlights the importance of close functional scrutiny of natural genetic variation within even relatively well-studied cis-regulatory regions.

  16. Human GRIN2B variants in neurodevelopmental disorders

    Directory of Open Access Journals (Sweden)

    Chun Hu

    2016-10-01

    Full Text Available The development of whole exome/genome sequencing technologies has given rise to an unprecedented volume of data linking patient genomic variability to brain disorder phenotypes. A surprising number of variants have been found in the N-methyl-d-aspartate receptor (NMDAR gene family, with the GRIN2B gene encoding the GluN2B subunit being implicated in many cases of neurodevelopmental disorders, which are psychiatric conditions originating in childhood and include language, motor, and learning disorders, autism spectrum disorder (ASD, attention deficit hyperactivity disorder (ADHD, developmental delay, epilepsy, and schizophrenia. The GRIN2B gene plays a crucial role in normal neuronal development and is important for learning and memory. Mutations in human GRIN2B were distributed throughout the entire gene in a number of patients with various neuropsychiatric and developmental disorders. Studies that provide functional analysis of variants are still lacking, however current analysis of de novo variants that segregate with disease cases such as intellectual disability, developmental delay, ASD or epileptic encephalopathies reveal altered NMDAR function. Here, we summarize the current reports of disease-associated variants in GRIN2B from patients with multiple neurodevelopmental disorders, and discuss implications, highlighting the importance of functional analysis and precision medicine therapies.

  17. Radioimmunological activity of 22K variant of human growth hormone

    International Nuclear Information System (INIS)

    Camillo, M.A.P.; Ribela, M.T.C.P.; Rogero, J.R.

    1986-01-01

    From a preparation of human growth hormone its integral variant (hGH-22K) was isolated by isoelectric focusing, having a pI of 5,20 and relative mobility (Rm) of 0,621 in the polyacrylamide gel electrophoresis. Several experiments for the characterization of the isolated variant were carried out. The immunological properties was tested by radioimmunoassay (RIE), in which the activity of the isolated variant and the activity of the total preparation were compared. The dose response-curves obtained by RIE were found to be considered parallels (p [pt

  18. Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients

    Science.gov (United States)

    Sadovnick, A. Dessa; Traboulsee, Anthony L.; Bernales, Cecily Q.; Ross, Jay P.; Forwell, Amanda L.; Yee, Irene M.; Guillot-Noel, Lena; Fontaine, Bertrand; Cournu-Rebeix, Isabelle; Alcina, Antonio; Fedetz, Maria; Izquierdo, Guillermo; Matesanz, Fuencisla; Hilven, Kelly; Dubois, Bénédicte; Goris, An; Astobiza, Ianire; Alloza, Iraide; Antigüedad, Alfredo; Vandenbroeck, Koen; Akkad, Denis A.; Aktas, Orhan; Blaschke, Paul; Buttmann, Mathias; Chan, Andrew; Epplen, Joerg T.; Gerdes, Lisa-Ann; Kroner, Antje; Kubisch, Christian; Kümpfel, Tania; Lohse, Peter; Rieckmann, Peter; Zettl, Uwe K.; Zipp, Frauke; Bertram, Lars; Lill, Christina M; Fernandez, Oscar; Urbaneja, Patricia; Leyva, Laura; Alvarez-Cermeño, Jose Carlos; Arroyo, Rafael; Garagorri, Aroa M.; García-Martínez, Angel; Villar, Luisa M.; Urcelay, Elena; Malhotra, Sunny; Montalban, Xavier; Comabella, Manuel; Berger, Thomas; Fazekas, Franz; Reindl, Markus; Schmied, Mascha C.; Zimprich, Alexander; Vilariño-Güell, Carles

    2016-01-01

    Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93–1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility. PMID:27194806

  19. Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients

    Directory of Open Access Journals (Sweden)

    A. Dessa Sadovnick

    2016-07-01

    Full Text Available Multiple sclerosis (MS is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D in plasminogen (PLG as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351 in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117, despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93–1.87. To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.

  20. Korean Variant Archive (KOVA): a reference database of genetic variations in the Korean population.

    Science.gov (United States)

    Lee, Sangmoon; Seo, Jihae; Park, Jinman; Nam, Jae-Yong; Choi, Ahyoung; Ignatius, Jason S; Bjornson, Robert D; Chae, Jong-Hee; Jang, In-Jin; Lee, Sanghyuk; Park, Woong-Yang; Baek, Daehyun; Choi, Murim

    2017-06-27

    Despite efforts to interrogate human genome variation through large-scale databases, systematic preference toward populations of Caucasian descendants has resulted in unintended reduction of power in studying non-Caucasians. Here we report a compilation of coding variants from 1,055 healthy Korean individuals (KOVA; Korean Variant Archive). The samples were sequenced to a mean depth of 75x, yielding 101 singleton variants per individual. Population genetics analysis demonstrates that the Korean population is a distinct ethnic group comparable to other discrete ethnic groups in Africa and Europe, providing a rationale for such independent genomic datasets. Indeed, KOVA conferred 22.8% increased variant filtering power in addition to Exome Aggregation Consortium (ExAC) when used on Korean exomes. Functional assessment of nonsynonymous variant supported the presence of purifying selection in Koreans. Analysis of copy number variants detected 5.2 deletions and 10.3 amplifications per individual with an increased fraction of novel variants among smaller and rarer copy number variable segments. We also report a list of germline variants that are associated with increased tumor susceptibility. This catalog can function as a critical addition to the pre-existing variant databases in pursuing genetic studies of Korean individuals.

  1. Methods for engineering polypeptide variants via somatic hypermutation and polypeptide made thereby

    Science.gov (United States)

    Tsien, Roger Y; Wang, Lei

    2015-01-13

    Methods using somatic hypermutation (SHM) for producing polypeptide and nucleic acid variants, and nucleic acids encoding such polypeptide variants are disclosed. Such variants may have desired properties. Also disclosed are novel polypeptides, such as improved fluorescent proteins, produced by the novel methods, and nucleic acids, vectors, and host cells comprising such vectors.

  2. Variant Philadelphia translocations with different breakpoints in six chronic myeloid leukemia patients

    Directory of Open Access Journals (Sweden)

    Dilhan Kuru

    2011-09-01

    Full Text Available Objective: The Philadelphia (Ph chromosome, consisting of the t(9;22(q34;q11 translocation, is observed in ~90% of patients with chronic myeloid leukemia (CML. Variant Ph translocations are observed in 5%-10% of CML patients. In variant translocations 3 and possibly more chromosomes are involved. Herein we report 6 CML patients with variant Ph translocations.Materials and Methods: Bone marrow samples were examined using conventional cytogenetic meth ods. Fluorescence in situ hybridization (FISH with whole-chromosome paints and BCR-ABL 1D probes were used to confirm and/or complement the findings, and identify rearrangements beyond the resolution of conventional cytogenetic methods. Results: Variant Ph translocations in the 6 patients were as follows: t(7;22(p22;q11, t(9;22;15(q34;q11;q22, t(15;22(p11;q11, t(1;9;22;3(q24;q34;q11;q21, t(12;22(p13;q11, and t(4;8;9;22(q11;q13;q34;q11.Conclusion: Among the patients, 3 had simple and 3 had complex variant Ph translocations. Two of the presented cases had variant Ph chromosomes not previously described, 1 of which had a new complex Ph translocation involving chromosomes 1, 3, 9, 22, and t(1;9;22;3(q24;q34;q11;q21 apart from a clone with a classical Ph, and the other case had variant Ph translocation with chromosomes 4, 8, 9, and 22, and t(4;8;9;22(q11;q13;q34;q11 full complex translocation. Number of studies reported that some patients with variant Ph translocation were poor responders to imatinib. All of our patients with variant Ph translocations had suboptimal responses to imatinib, denoting a poor prognosis also. Variant Ph translocations may be important as they are associated with prognosis and therapy for CML patients.

  3. ATM variants and cancer risk in breast cancer patients from Southern Finland

    Directory of Open Access Journals (Sweden)

    Aittomäki Kristiina

    2006-08-01

    Full Text Available Abstract Background Individuals heterozygous for germline ATM mutations have been reported to have an increased risk for breast cancer but the role for ATM genetic variants for breast cancer risk has remained unclear. Recently, a common ATM variant, ATMivs38 -8T>C in cis with the ATMex39 5557G>A (D1853N variant, was suggested to associate with bilateral breast cancer among familial breast cancer patients from Northern Finland. We have here evaluated the 5557G>A and ivs38-8T>C variants in an extensive case-control association analysis. We also aimed to investigate whether there are other ATM mutations or variants contributing to breast cancer risk in our population. Methods Two common ATM variants, 5557G>A and ivs38-8T>C, previously suggested to associate with bilateral breast cancer, were genotyped in an extensive set of 786 familial and 884 unselected breast cancer cases as well as 708 healthy controls. We also screened the entire coding region and exon-intron boundaries of the ATM gene in 47 familial breast cancer patients and constructed haplotypes of the patients. The identified variants were also evaluated for increased breast cancer risk among additional breast cancer cases and controls. Results Neither of the two common variants, 5557G>A and ivs38-8T>C, nor any haplotype containing them, was significantly associated with breast cancer risk, bilateral breast cancer or multiple primary cancers in any of the patient groups or subgoups. Three rare missense alterations and one intronic change were each found in only one patient of over 250 familial patients studied and not among controls. The fourth missense alteration studied further was found with closely similar frequencies in over 600 familial cases and controls. Conclusion Altogether, our results suggest very minor effect, if any, of ATM genetic variants on familial breast cancer in Southern Finland. Our results do not support association of the 5557G>A or ivs38-8T>C variant with

  4. eCD4-Ig variants that more potently neutralize HIV-1.

    Science.gov (United States)

    Fetzer, Ina; Gardner, Matthew R; Davis-Gardner, Meredith E; Prasad, Neha R; Alfant, Barnett; Weber, Jesse A; Farzan, Michael

    2018-03-28

    The HIV-1 entry inhibitor eCD4-Ig is a fusion of CD4-Ig and a coreceptor-mimetic peptide. eCD4-Ig is markedly more potent than CD4-Ig, with neutralization efficiencies approaching those of HIV-1 broadly neutralizing antibodies (bNAbs). However, unlike bNAbs, eCD4-Ig neutralizes all HIV-1, HIV-2 and SIV isolates that it has been tested against, suggesting that it may be useful in clinical settings where antibody escape is a concern. Here we characterize three new eCD4-Ig variants, each with different architectures and each utilizing D1.22, a stabilized form of CD4 domain 1. These variants were 10- to 20-fold more potent than our original eCD4-Ig variant, with a construct bearing four D1.22 domains (eD1.22-HL-Ig) exhibiting the greatest potency. However, this variant mediated less efficient antibody-dependent cell-mediated cytotoxicity (ADCC) activity than eCD4-Ig itself or several other eCD4-Ig variants, including the smallest variant (eD1.22-Ig). A variant with the same architecture as original eCD4-Ig (eD1.22-D2-Ig) showed modestly higher thermal stability and best prevented promotion of infection of CCR5-positive, CD4-negative cells. All three variants, and eCD4-Ig itself, mediated more efficient shedding of the HIV-1 envelope glycoprotein gp120 than did CD4-Ig. Finally, we show that only three D1.22 mutations contributed to the potency of eD1.22-D2-Ig, and that introduction of these changes into eCD4-Ig resulted in a variant 9-fold more potent than eCD4-Ig and 2-fold more potent than eD1.22-D2-Ig. These studies will assist in developing eCD4-Ig variants with properties optimized for prophylaxis, therapy, and cure applications. IMPORTANCE HIV-1 bNAbs have properties different from antiretroviral compounds. Specifically, antibodies can enlist immune effector cells to eliminate infected cells, whereas antiretroviral compounds simply interfere with various steps in the viral lifecycle. Unfortunately, HIV-1 is adept at evading antibody recognition, limiting the

  5. A novel multi-variant epitope ensemble vaccine against avian leukosis virus subgroup J.

    Science.gov (United States)

    Wang, Xiaoyu; Zhou, Defang; Wang, Guihua; Huang, Libo; Zheng, Qiankun; Li, Chengui; Cheng, Ziqiang

    2017-12-04

    The hypervariable antigenicity and immunosuppressive features of avian leukosis virus subgroup J (ALV-J) has led to great challenges to develop effective vaccines. Epitope vaccine will be a perspective trend. Previously, we identified a variant antigenic neutralizing epitope in hypervariable region 1 (hr1) of ALV-J, N-LRDFIA/E/TKWKS/GDDL/HLIRPYVNQS-C. BLAST analysis showed that the mutation of A, E, T and H in this epitope cover 79% of all ALV-J strains. Base on this data, we designed a multi-variant epitope ensemble vaccine comprising the four mutation variants linked with glycine and serine. The recombinant multi-variant epitope gene was expressed in Escherichia coli BL21. The expressed protein of the variant multi-variant epitope gene can react with positive sera and monoclonal antibodies of ALV-J, while cannot react with ALV-J negative sera. The multi-variant epitope vaccine that conjugated Freund's adjuvant complete/incomplete showed high immunogenicity that reached the titer of 1:64,000 at 42 days post immunization and maintained the immune period for at least 126 days in SPF chickens. Further, we demonstrated that the antibody induced by the variant multi-variant ensemble epitope vaccine recognized and neutralized different ALV-J strains (NX0101, TA1, WS1, BZ1224 and BZ4). Protection experiment that was evaluated by clinical symptom, viral shedding, weight gain, gross and histopathology showed 100% chickens that inoculated the multi-epitope vaccine were well protected against ALV-J challenge. The result shows a promising multi-variant epitope ensemble vaccine against hypervariable viruses in animals. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Novel genetic variants in miR-191 gene and familial ovarian cancer

    International Nuclear Information System (INIS)

    Shen, Jie; DiCioccio, Richard; Odunsi, Kunle; Lele, Shashikant B; Zhao, Hua

    2010-01-01

    Half of the familial aggregation of ovarian cancer can't be explained by any known risk genes, suggesting the existence of other genetic risk factors. Some of these unknown factors may not be traditional protein encoding genes. MicroRNA (miRNA) plays a critical role in tumorigenesis, but it is still unknown if variants in miRNA genes lead to predisposition to cancer. Considering the fact that miRNA regulates a number of tumor suppressor genes (TSGs) and oncogenes, genetic variations in miRNA genes could affect the levels of expression of TSGs or oncogenes and, thereby, cancer risk. To test this hypothesis in familial ovarian cancer, we screened for genetic variants in thirty selected miRNA genes, which are predicted to regulate key ovarian cancer genes and are reported to be misexpressed in ovarian tumor tissues, in eighty-three patients with familial ovarian cancer. All of the patients are non-carriers of any known BRCA1/2 or mismatch repair (MMR) gene mutations. Seven novel genetic variants were observed in four primary or precursor miRNA genes. Among them, three rare variants were found in the precursor or primary precursor of the miR-191 gene. In functional assays, the one variant located in the precursor of miR-191 resulted in conformational changes in the predicted secondary structures, and consequently altered the expression of mature miR-191. In further analysis, we found that this particular variant exists in five family members who had ovarian cancer. Our findings suggest that there are novel genetic variants in miRNA genes, and those certain genetic variants in miRNA genes can affect the expression of mature miRNAs and, consequently, might alter the regulation of TSGs or oncogenes. Additionally, the variant might be potentially associated with the development of familial ovarian cancer

  7. Lack of Association of CD55 Receptor Genetic Variants and Severe Malaria in Ghanaian Children

    Directory of Open Access Journals (Sweden)

    Kathrin Schuldt

    2017-03-01

    Full Text Available In a recent report, the cellular receptor CD55 was identified as a molecule essential for the invasion of human erythrocytes by Plasmodium falciparum, the causal agent of the most severe form of malaria. As this invasion process represents a critical step during infection with the parasite, it was hypothesized that genetic variants in the gene could affect severe malaria (SM susceptibility. We performed high-resolution variant discovery of rare and common genetic variants in the human CD55 gene. Association testing of these variants in over 1700 SM cases and unaffected control individuals from the malaria-endemic Ashanti Region in Ghana, West Africa, were performed on the basis of single variants, combined rare variant analyses, and reconstructed haplotypes. A total of 26 genetic variants were detected in coding and regulatory regions of CD55. Five variants were previously unknown. None of the single variants, rare variants, or haplotypes showed evidence for association with SM or P. falciparum density. Here, we present the first comprehensive analysis of variation in the CD55 gene in the context of SM and show that genetic variants present in a Ghanaian study group appear not to influence susceptibility to the disease.

  8. [Specificities of the logopenic variant of primary progressive aphasia].

    Science.gov (United States)

    Magnin, E; Teichmann, M; Martinaud, O; Moreaud, O; Ryff, I; Belliard, S; Pariente, J; Moulin, T; Vandel, P; Démonet, J-F

    2015-01-01

    The logopenic variant of primary progressive aphasia is a syndrome with neuropsychological and linguistic specificities, including phonological loop impairment for which diagnosis is currently mainly based on the exclusion of the two other variants, semantic and nonfluent/agrammatic primary progressive aphasia. The syndrome may be underdiagnosed due (1) to mild language difficulties during the early stages of the disease or (2) to being mistaken for mild cognitive impairment or Alzheimer's disease when the evaluation of episodic memory is based on verbal material and (3) finally, it is not uncommon that the disorders are attributed to psychiatric co-morbidities such as, for example, anxiety. Moreover, compared to other variants of primary progressive aphasia, brain abnormalities are different. The left temporoparietal junction is initially affected. Neuropathology and biomarkers (cerebrospinal fluid, molecular amyloid nuclear imaging) frequently reveal Alzheimer's disease. Consequently this variant of primary progressive aphasia does not fall under the traditional concept of frontotemporal lobar degeneration. These distinctive features highlight the utility of correct diagnosis, classification, and use of biomarkers to show the neuropathological processes underlying logopenic primary progressive aphasia. The logopenic variant of primary progressive aphasia is a specific form of Alzheimer's disease frequently presenting a rapid decline; specific linguistic therapies are needed. Further investigation of this syndrome is needed to refine screening, improve diagnostic criteria and better understand the epidemiology and the biological mechanisms involved. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  9. Burden of rare variants in ALS genes influences survival in familial and sporadic ALS.

    Science.gov (United States)

    Pang, Shirley Yin-Yu; Hsu, Jacob Shujui; Teo, Kay-Cheong; Li, Yan; Kung, Michelle H W; Cheah, Kathryn S E; Chan, Danny; Cheung, Kenneth M C; Li, Miaoxin; Sham, Pak-Chung; Ho, Shu-Leong

    2017-10-01

    Genetic variants are implicated in the development of amyotrophic lateral sclerosis (ALS), but it is unclear whether the burden of rare variants in ALS genes has an effect on survival. We performed whole genome sequencing on 8 familial ALS (FALS) patients with superoxide dismutase 1 (SOD1) mutation and whole exome sequencing on 46 sporadic ALS (SALS) patients living in Hong Kong and found that 67% had at least 1 rare variant in the exons of 40 ALS genes; 22% had 2 or more. Patients with 2 or more rare variants had lower probability of survival than patients with 0 or 1 variant (p = 0.001). After adjusting for other factors, each additional rare variant increased the risk of respiratory failure or death by 60% (p = 0.0098). The presence of the rare variant was associated with the risk of ALS (Odds ratio 1.91, 95% confidence interval 1.03-3.61, p = 0.03), and ALS patients had higher rare variant burden than controls (MB, p = 0.004). Our findings support an oligogenic basis with the burden of rare variants affecting the development and survival of ALS. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  10. GCKR variants increase triglycerides while protecting from insulin resistance in Chinese children.

    Science.gov (United States)

    Shen, Yue; Wu, Lijun; Xi, Bo; Liu, Xin; Zhao, Xiaoyuan; Cheng, Hong; Hou, Dongqing; Wang, Xingyu; Mi, Jie

    2013-01-01

    Variants in gene encoding glucokinase regulator protein (GCKR) were found to have converse effects on triglycerides and glucose metabolic traits. We aimed to investigate the influence of GCKR variants for triglycerides and glucose metabolic traits in Chinese children and adults. We genotyped two GCKR variants rs1260326 and rs1260333 in children and adults, and analyzed the association between two variants and triglycerides, glucose, insulin and HOMA-IR using linear regression model, and estimated the effect on insulin resistance using logistic regression model. Rs1260326 and rs1260333 associated with increased triglycerides in children and adults (ptriglycerides in Chinese children and adults. Triglycerides-increasing alleles of GCKR variants reduce insulin and HOMA-IR index, and protect from insulin resistance in children. Our results suggested GCKR has an effect on development of insulin resistance in Chinese children.

  11. BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer.

    OpenAIRE

    Shimelis, Hermela; Mesman, Romy LS; Von, Nicolai Catharina; Ehlen, Asa; Guidugli, Lucia; Martin, Charlotte; Calléja, Fabienne MGR; Meeks, Huong; Hallberg, Emily; Hinton, Jamie; Lilyquist, Jenna; Hu, Chunling; Aalfs, Cora M; Aittomäki, Kristiina; Andrulis, Irene

    2017-01-01

    Breast cancer risks conferred by many germline missense variants in the $\\textit{BRCA1}$ and $\\textit{BRCA2}$ genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine ...

  12. Collapsing variant of focal segmental glomerulosclerosis in children = Variante colapsante de la glomeruloesclerosis focal y segmentaria en niños

    Directory of Open Access Journals (Sweden)

    Jonh Fredy Nieto Ríos

    2013-10-01

    Full Text Available Focal segmental glomerulosclerosis (FSGS collapsing variant refers to a renal lesion that may be idiopathic or associated to some factors, characterized by glomerular collapse leading to cortico-resistant nephrotic syndrome and chronic progressive renal failure. This glomerulopathy has been scarcely studied in children, but in this age group most cases are idiopathic. In this paper we present a report of 6 cases of collapsing variant of FSGS in children no associated to HIV, which were resistant to immunosuppressive management and with a high mortality

  13. Non-coding keratin variants associate with liver fibrosis progression in patients with hemochromatosis.

    Directory of Open Access Journals (Sweden)

    Pavel Strnad

    Full Text Available BACKGROUND: Keratins 8 and 18 (K8/K18 are intermediate filament proteins that protect the liver from various forms of injury. Exonic K8/K18 variants associate with adverse outcome in acute liver failure and with liver fibrosis progression in patients with chronic hepatitis C infection or primary biliary cirrhosis. Given the association of K8/K18 variants with end-stage liver disease and progression in several chronic liver disorders, we studied the importance of keratin variants in patients with hemochromatosis. METHODS: The entire K8/K18 exonic regions were analyzed in 162 hemochromatosis patients carrying homozygous C282Y HFE (hemochromatosis gene mutations. 234 liver-healthy subjects were used as controls. Exonic regions were PCR-amplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. Previously-generated transgenic mice overexpressing K8 G62C were studied for their susceptibility to iron overload. Susceptibility to iron toxicity of primary hepatocytes that express K8 wild-type and G62C was also assessed. RESULTS: We identified amino-acid-altering keratin heterozygous variants in 10 of 162 hemochromatosis patients (6.2% and non-coding heterozygous variants in 6 additional patients (3.7%. Two novel K8 variants (Q169E/R275W were found. K8 R341H was the most common amino-acid altering variant (4 patients, and exclusively associated with an intronic KRT8 IVS7+10delC deletion. Intronic, but not amino-acid-altering variants associated with the development of liver fibrosis. In mice, or ex vivo, the K8 G62C variant did not affect iron-accumulation in response to iron-rich diet or the extent of iron-induced hepatocellular injury. CONCLUSION: In patients with hemochromatosis, intronic but not exonic K8/K18 variants associate with liver fibrosis development.

  14. Mesotrypsin Signature Mutation in a Chymotrypsin C (CTRC) Variant Associated with Chronic Pancreatitis.

    Science.gov (United States)

    Szabó, András; Ludwig, Maren; Hegyi, Eszter; Szépeová, Renata; Witt, Heiko; Sahin-Tóth, Miklós

    2015-07-10

    Human chymotrypsin C (CTRC) protects against pancreatitis by degrading trypsinogen and thereby curtailing harmful intra-pancreatic trypsinogen activation. Loss-of-function mutations in CTRC increase the risk for chronic pancreatitis. Here we describe functional analysis of eight previously uncharacterized natural CTRC variants tested for potential defects in secretion, proteolytic stability, and catalytic activity. We found that all variants were secreted from transfected cells normally, and none suffered proteolytic degradation by trypsin. Five variants had normal enzymatic activity, whereas variant p.R29Q was catalytically inactive due to loss of activation by trypsin and variant p.S239C exhibited impaired activity possibly caused by disulfide mispairing. Surprisingly, variant p.G214R had increased activity on a small chromogenic peptide substrate but was markedly defective in cleaving bovine β-casein or the natural CTRC substrates human cationic trypsinogen and procarboxypeptidase A1. Mutation p.G214R is analogous to the evolutionary mutation in human mesotrypsin, which rendered this trypsin isoform resistant to proteinaceous inhibitors and conferred its ability to cleave these inhibitors. Similarly to the mesotrypsin phenotype, CTRC variant p.G214R was inhibited poorly by eglin C, ecotin, or a CTRC-specific variant of SGPI-2, and it readily cleaved the reactive-site peptide bonds in eglin C and ecotin. We conclude that CTRC variants p.R29Q, p.G214R, and p.S239C are risk factors for chronic pancreatitis. Furthermore, the mesotrypsin-like CTRC variant highlights how the same natural mutation in homologous pancreatic serine proteases can evolve a new physiological role or lead to pathology, determined by the biological context of protease function. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. A global evolutionary and metabolic analysis of human obesity gene risk variants.

    Science.gov (United States)

    Castillo, Joseph J; Hazlett, Zachary S; Orlando, Robert A; Garver, William S

    2017-09-05

    It is generally accepted that the selection of gene variants during human evolution optimized energy metabolism that now interacts with our obesogenic environment to increase the prevalence of obesity. The purpose of this study was to perform a global evolutionary and metabolic analysis of human obesity gene risk variants (110 human obesity genes with 127 nearest gene risk variants) identified using genome-wide association studies (GWAS) to enhance our knowledge of early and late genotypes. As a result of determining the mean frequency of these obesity gene risk variants in 13 available populations from around the world our results provide evidence for the early selection of ancestral risk variants (defined as selection before migration from Africa) and late selection of derived risk variants (defined as selection after migration from Africa). Our results also provide novel information for association of these obesity genes or encoded proteins with diverse metabolic pathways and other human diseases. The overall results indicate a significant differential evolutionary pattern for the selection of obesity gene ancestral and derived risk variants proposed to optimize energy metabolism in varying global environments and complex association with metabolic pathways and other human diseases. These results are consistent with obesity genes that encode proteins possessing a fundamental role in maintaining energy metabolism and survival during the course of human evolution. Copyright © 2017. Published by Elsevier B.V.

  16. VIPER: a web application for rapid expert review of variant calls.

    Science.gov (United States)

    Wöste, Marius; Dugas, Martin

    2018-01-15

    With the rapid development in next-generation sequencing, cost and time requirements for genomic sequencing are decreasing, enabling applications in many areas such as cancer research. Many tools have been developed to analyze genomic variation ranging from single nucleotide variants to whole chromosomal aberrations. As sequencing throughput increases, the number of variants called by such tools also grows. Often employed manual inspection of such calls is thus becoming a time-consuming procedure. We developed the Variant InsPector and Expert Rating tool (VIPER) to speed up this process by integrating the Integrative Genomics Viewer into a web application. Analysts can then quickly iterate through variants, apply filters and make decisions based on the generated images and variant metadata. VIPER was successfully employed in analyses with manual inspection of more than 10,000 calls. VIPER is implemented in Java and Javascript and is freely available at https://github.com/MarWoes/viper. Marius.Woeste@uni-muenster.de. Supplementary data are available at Bioinformatics online. © The Author (2018). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  17. Annotating DNA variants is the next major goal for human genetics.

    Science.gov (United States)

    Cutting, Garry R

    2014-01-02

    Clinical genetic testing has undergone a dramatic transformation in the past two decades. Diagnostic laboratories that previously tested for well-established disease-causing DNA variants in a handful of genes have evolved into sequencing factories identifying thousands of variants of known and unknown medical consequence. Sorting out what does and does not cause disease in our genomes is the next great challenge in making genetics a central feature of healthcare. I propose that closing the gap in our ability to interpret variation responsible for Mendelian disorders provides a grand and unprecedented opportunity for geneticists. Human geneticists are well placed to coordinate a systematic evaluation of variants in collaboration with basic scientists and clinicians. Sharing of knowledge, data, methods, and tools will aid both researchers and healthcare workers in achieving their common goal of defining the pathogenic potential of variants. Generation of variant annotations will inform genetic testing and will deepen our understanding of gene and protein function, thereby aiding the search for molecular targeted therapies. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  18. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

    Science.gov (United States)

    Beecham, Ashley H; Patsopoulos, Nikolaos A; Xifara, Dionysia K; Davis, Mary F; Kemppinen, Anu; Cotsapas, Chris; Shahi, Tejas S; Spencer, Chris; Booth, David; Goris, An; Oturai, Annette; Saarela, Janna; Fontaine, Bertrand; Hemmer, Bernhard; Martin, Claes; Zipp, Frauke; D’alfonso, Sandra; Martinelli-Boneschi, Filippo; Taylor, Bruce; Harbo, Hanne F; Kockum, Ingrid; Hillert, Jan; Olsson, Tomas; Ban, Maria; Oksenberg, Jorge R; Hintzen, Rogier; Barcellos, Lisa F; Agliardi, Cristina; Alfredsson, Lars; Alizadeh, Mehdi; Anderson, Carl; Andrews, Robert; Søndergaard, Helle Bach; Baker, Amie; Band, Gavin; Baranzini, Sergio E; Barizzone, Nadia; Barrett, Jeffrey; Bellenguez, Céline; Bergamaschi, Laura; Bernardinelli, Luisa; Berthele, Achim; Biberacher, Viola; Binder, Thomas M C; Blackburn, Hannah; Bomfim, Izaura L; Brambilla, Paola; Broadley, Simon; Brochet, Bruno; Brundin, Lou; Buck, Dorothea; Butzkueven, Helmut; Caillier, Stacy J; Camu, William; Carpentier, Wassila; Cavalla, Paola; Celius, Elisabeth G; Coman, Irène; Comi, Giancarlo; Corrado, Lucia; Cosemans, Leentje; Cournu-Rebeix, Isabelle; Cree, Bruce A C; Cusi, Daniele; Damotte, Vincent; Defer, Gilles; Delgado, Silvia R; Deloukas, Panos; di Sapio, Alessia; Dilthey, Alexander T; Donnelly, Peter; Dubois, Bénédicte; Duddy, Martin; Edkins, Sarah; Elovaara, Irina; Esposito, Federica; Evangelou, Nikos; Fiddes, Barnaby; Field, Judith; Franke, Andre; Freeman, Colin; Frohlich, Irene Y; Galimberti, Daniela; Gieger, Christian; Gourraud, Pierre-Antoine; Graetz, Christiane; Graham, Andrew; Grummel, Verena; Guaschino, Clara; Hadjixenofontos, Athena; Hakonarson, Hakon; Halfpenny, Christopher; Hall, Gillian; Hall, Per; Hamsten, Anders; Harley, James; Harrower, Timothy; Hawkins, Clive; Hellenthal, Garrett; Hillier, Charles; Hobart, Jeremy; Hoshi, Muni; Hunt, Sarah E; Jagodic, Maja; Jelčić, Ilijas; Jochim, Angela; Kendall, Brian; Kermode, Allan; Kilpatrick, Trevor; Koivisto, Keijo; Konidari, Ioanna; Korn, Thomas; Kronsbein, Helena; Langford, Cordelia; Larsson, Malin; Lathrop, Mark; Lebrun-Frenay, Christine; Lechner-Scott, Jeannette; Lee, Michelle H; Leone, Maurizio A; Leppä, Virpi; Liberatore, Giuseppe; Lie, Benedicte A; Lill, Christina M; Lindén, Magdalena; Link, Jenny; Luessi, Felix; Lycke, Jan; Macciardi, Fabio; Männistö, Satu; Manrique, Clara P; Martin, Roland; Martinelli, Vittorio; Mason, Deborah; Mazibrada, Gordon; McCabe, Cristin; Mero, Inger-Lise; Mescheriakova, Julia; Moutsianas, Loukas; Myhr, Kjell-Morten; Nagels, Guy; Nicholas, Richard; Nilsson, Petra; Piehl, Fredrik; Pirinen, Matti; Price, Siân E; Quach, Hong; Reunanen, Mauri; Robberecht, Wim; Robertson, Neil P; Rodegher, Mariaemma; Rog, David; Salvetti, Marco; Schnetz-Boutaud, Nathalie C; Sellebjerg, Finn; Selter, Rebecca C; Schaefer, Catherine; Shaunak, Sandip; Shen, Ling; Shields, Simon; Siffrin, Volker; Slee, Mark; Sorensen, Per Soelberg; Sorosina, Melissa; Sospedra, Mireia; Spurkland, Anne; Strange, Amy; Sundqvist, Emilie; Thijs, Vincent; Thorpe, John; Ticca, Anna; Tienari, Pentti; van Duijn, Cornelia; Visser, Elizabeth M; Vucic, Steve; Westerlind, Helga; Wiley, James S; Wilkins, Alastair; Wilson, James F; Winkelmann, Juliane; Zajicek, John; Zindler, Eva; Haines, Jonathan L; Pericak-Vance, Margaret A; Ivinson, Adrian J; Stewart, Graeme; Hafler, David; Hauser, Stephen L; Compston, Alastair; McVean, Gil; De Jager, Philip; Sawcer, Stephen; McCauley, Jacob L

    2013-01-01

    Using the ImmunoChip custom genotyping array, we analysed 14,498 multiple sclerosis subjects and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (p-value multiple sclerosis subjects and 26,703 healthy controls. In these 80,094 individuals of European ancestry we identified 48 new susceptibility variants (p-value multiple sclerosis risk variants in 103 discrete loci outside of the Major Histocompatibility Complex. With high resolution Bayesian fine-mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalogue of multiple sclerosis risk variants and illustrates the value of fine-mapping in the resolution of GWAS signals. PMID:24076602

  19. [Genetic variants in miRNAs and its association with breast cancer].

    Science.gov (United States)

    Méndez-Gómez, Susana; Ruiz Esparza-Garrido, Ruth; Velázquez-Flores, Miguel; Dolores-Vergara, Maria; Salamanca-Gómez, Fabio; Arenas-Aranda, Diego Julio

    2014-01-01

    In Mexico, breast cancer represents the first cause of cancer death in females. At the molecular level, non-coding RNAs and especially microRNAs have played an important role in the origin and development of this neoplasm In the Anglo-Saxon population, diverse genetic variants in microRNA genes and in their targets are associated with the development of this disease. In the Mexican population it is not known if these or other variants exist. Identification of these or new variants in our population is fundamental in order to have a better understanding of cancer development and to help establish a better diagnostic strategy. DNA was isolated from mammary tumors, adjacent tissue and peripheral blood of Mexican females with or without cancer. From DNA, five microRNA genes and three of their targets were amplified and sequenced. Genetic variants associated with breast cancer in an Anglo- Saxon population have been previously identified in these sequences. In the samples studied we identified seven single nucleotide polymorphisms (SNPs). Two had not been previously described and were identified only in women with cancer. The new variants may be genetic predisposition factors for the development of breast cancer in our population. Further experiments are needed to determine the involvement of these variants in the development, establishment and progression of breast cancer.

  20. Regularized rare variant enrichment analysis for case-control exome sequencing data.

    Science.gov (United States)

    Larson, Nicholas B; Schaid, Daniel J

    2014-02-01

    Rare variants have recently garnered an immense amount of attention in genetic association analysis. However, unlike methods traditionally used for single marker analysis in GWAS, rare variant analysis often requires some method of aggregation, since single marker approaches are poorly powered for typical sequencing study sample sizes. Advancements in sequencing technologies have rendered next-generation sequencing platforms a realistic alternative to traditional genotyping arrays. Exome sequencing in particular not only provides base-level resolution of genetic coding regions, but also a natural paradigm for aggregation via genes and exons. Here, we propose the use of penalized regression in combination with variant aggregation measures to identify rare variant enrichment in exome sequencing data. In contrast to marginal gene-level testing, we simultaneously evaluate the effects of rare variants in multiple genes, focusing on gene-based least absolute shrinkage and selection operator (LASSO) and exon-based sparse group LASSO models. By using gene membership as a grouping variable, the sparse group LASSO can be used as a gene-centric analysis of rare variants while also providing a penalized approach toward identifying specific regions of interest. We apply extensive simulations to evaluate the performance of these approaches with respect to specificity and sensitivity, comparing these results to multiple competing marginal testing methods. Finally, we discuss our findings and outline future research. © 2013 WILEY PERIODICALS, INC.

  1. Rare variants in RTEL1 are associated with familial interstitial pneumonia.

    Science.gov (United States)

    Cogan, Joy D; Kropski, Jonathan A; Zhao, Min; Mitchell, Daphne B; Rives, Lynette; Markin, Cheryl; Garnett, Errine T; Montgomery, Keri H; Mason, Wendi R; McKean, David F; Powers, Julia; Murphy, Elissa; Olson, Lana M; Choi, Leena; Cheng, Dong-Sheng; Blue, Elizabeth Marchani; Young, Lisa R; Lancaster, Lisa H; Steele, Mark P; Brown, Kevin K; Schwarz, Marvin I; Fingerlin, Tasha E; Schwartz, David A; Lawson, William E; Loyd, James E; Zhao, Zhongming; Phillips, John A; Blackwell, Timothy S

    2015-03-15

    Up to 20% of cases of idiopathic interstitial pneumonia cluster in families, comprising the syndrome of familial interstitial pneumonia (FIP); however, the genetic basis of FIP remains uncertain in most families. To determine if new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis. Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing from genomic DNA. Candidate rare variants were confirmed by Sanger sequencing, and cosegregation analysis was performed in families, followed by additional sequencing of affected individuals from another 163 kindreds. We identified a potentially damaging rare variant in the gene encoding for regulator of telomere elongation helicase 1 (RTEL1) that segregated with disease and was associated with very short telomeres in peripheral blood mononuclear cells in 1 of 25 families in our original whole-exome sequencing cohort. Evaluation of affected individuals in 163 additional kindreds revealed another eight families (4.7%) with heterozygous rare variants in RTEL1 that segregated with clinical FIP. Probands and unaffected carriers of these rare variants had short telomeres (RTEL1 function. Rare loss-of-function variants in RTEL1 represent a newly defined genetic predisposition for FIP, supporting the importance of telomere-related pathways in pulmonary fibrosis.

  2. Effects of brand variants on smokers' choice behaviours and risk perceptions.

    Science.gov (United States)

    Hoek, Janet; Gendall, Philip; Eckert, Christine; Kemper, Joya; Louviere, Jordan

    2016-03-01

    Australian tobacco companies have introduced evocative variant names that could re-create the aspirational connotations plain packaging aims to remove. To inform future regulation, we explored how brand descriptors affected smokers' responses to plain packs featuring different variant name combinations. An online survey of 254 daily smokers or social smokers aged between 18 and 34 used a within-subjects best-worst experiment to estimate the relative effects of variant names. A 2×4×4×4 design contained four attributes: quality (premium or none), taste (smooth, fine, rich or none) connotation (classic, midnight, infinite or none) and colour (red, blue, white or none). In a between-subjects component, respondents evaluated one of two alternative packs according to its perceived harm and ease of quitting. The most important variant attribute was connotation, followed by taste, colour and quality; within these attributes, the most attractive descriptors were 'classic' and 'smooth'. We identified four distinct segments that differed significantly in their sociodemographic attributes and variant preferences, although not in their perceptions of the harm or quitting ease associated with two different variants. Some descriptors significantly enhance the appeal of tobacco products among different groups of smokers and may undermine plain packaging's dissuasive intent. Policymakers should explicitly regulate variant names to avoid the 'poetry on a package' evident in Australia. Options include disallowing new descriptors, limiting the number of descriptors permitted or banning descriptors altogether. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  3. Imputation of variants from the 1000 Genomes Project modestly improves known associations and can identify low-frequency variant-phenotype associations undetected by HapMap based imputation.

    Science.gov (United States)

    Wood, Andrew R; Perry, John R B; Tanaka, Toshiko; Hernandez, Dena G; Zheng, Hou-Feng; Melzer, David; Gibbs, J Raphael; Nalls, Michael A; Weedon, Michael N; Spector, Tim D; Richards, J Brent; Bandinelli, Stefania; Ferrucci, Luigi; Singleton, Andrew B; Frayling, Timothy M

    2013-01-01

    Genome-wide association (GWA) studies have been limited by the reliance on common variants present on microarrays or imputable from the HapMap Project data. More recently, the completion of the 1000 Genomes Project has provided variant and haplotype information for several million variants derived from sequencing over 1,000 individuals. To help understand the extent to which more variants (including low frequency (1% ≤ MAF 1000 Genomes imputation, respectively, and 9 and 11 that reached a stricter, likely conservative, threshold of P1000 Genomes genotype data modestly improved the strength of known associations. Of 20 associations detected at P1000 Genomes imputed data and one was nominally more strongly associated in HapMap imputed data. We also detected an association between a low frequency variant and phenotype that was previously missed by HapMap based imputation approaches. An association between rs112635299 and alpha-1 globulin near the SERPINA gene represented the known association between rs28929474 (MAF = 0.007) and alpha1-antitrypsin that predisposes to emphysema (P = 2.5×10(-12)). Our data provide important proof of principle that 1000 Genomes imputation will detect novel, low frequency-large effect associations.

  4. Maternal inheritance and mitochondrial DNA variants in familial Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Pfeiffer Ronald F

    2010-04-01

    Full Text Available Abstract Background Mitochondrial function is impaired in Parkinson's disease (PD and may contribute to the pathogenesis of PD, but the causes of mitochondrial impairment in PD are unknown. Mitochondrial dysfunction is recapitulated in cell lines expressing mitochondrial DNA (mtDNA from PD patients, implicating mtDNA variants or mutations, though the role of mtDNA variants or mutations in PD risk remains unclear. We investigated the potential contribution of mtDNA variants or mutations to the risk of PD. Methods We examined the possibility of a maternal inheritance bias as well as the association between mitochondrial haplogroups and maternal inheritance and disease risk in a case-control study of 168 multiplex PD families in which the proband and one parent were diagnosed with PD. 2-tailed Fisher Exact Tests and McNemar's tests were used to compare allele frequencies, and a t-test to compare ages of onset. Results The frequency of affected mothers of the proband with PD (83/167, 49.4% was not significantly different from the frequency of affected females of the proband generation (115/259, 44.4% (Odds Ratio 1.22; 95%CI 0.83 - 1.81. After correcting for multiple tests, there were no significant differences in the frequencies of mitochondrial haplogroups or of the 10398G complex I gene polymorphism in PD patients compared to controls, and no significant associations with age of onset of PD. Mitochondrial haplogroup and 10398G polymorphism frequencies were similar in probands having an affected father as compared to probands having an affected mother. Conclusions These data fail to demonstrate a bias towards maternal inheritance in familial PD. Consistent with this, we find no association of common haplogroup-defining mtDNA variants or for the 10398G variant with the risk of PD. However, these data do not exclude a role for mtDNA variants in other populations, and it remains possible that other inherited mitochondrial DNA variants, or somatic m

  5. Systematic identification of regulatory variants associated with cancer risk.

    Science.gov (United States)

    Liu, Song; Liu, Yuwen; Zhang, Qin; Wu, Jiayu; Liang, Junbo; Yu, Shan; Wei, Gong-Hong; White, Kevin P; Wang, Xiaoyue

    2017-10-23

    Most cancer risk-associated single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) are noncoding and it is challenging to assess their functional impacts. To systematically identify the SNPs that affect gene expression by modulating activities of distal regulatory elements, we adapt the self-transcribing active regulatory region sequencing (STARR-seq) strategy, a high-throughput technique to functionally quantify enhancer activities. From 10,673 SNPs linked with 996 cancer risk-associated SNPs identified in previous GWAS studies, we identify 575 SNPs in the fragments that positively regulate gene expression, and 758 SNPs in the fragments with negative regulatory activities. Among them, 70 variants are regulatory variants for which the two alleles confer different regulatory activities. We analyze in depth two regulatory variants-breast cancer risk SNP rs11055880 and leukemia risk-associated SNP rs12142375-and demonstrate their endogenous regulatory activities on expression of ATF7IP and PDE4B genes, respectively, using a CRISPR-Cas9 approach. By identifying regulatory variants associated with cancer susceptibility and studying their molecular functions, we hope to help the interpretation of GWAS results and provide improved information for cancer risk assessment.

  6. Macro-economic effects of two policy variants to reduce greenhouse gas emission

    International Nuclear Information System (INIS)

    Vromans, M.W.A.M.

    1998-10-01

    The macro-economic effects of two variants for reducing CO2-emissions by yearly 2% in the period 2000-2020 have been calculated. Regulations as limiting the maximum speed to 90 km/h on motorways and lowering the standards of energy use of houses form an important part of variant 1. In the second variant the competitive market policy plays a more important role. An increase of the existing small-user energy tax to four times the current level and an introduction of tradeable reduction certificates are among the policy measures. In both variants, but in variant 2 more than in variant 1, backstop-options, e.g. import of biomass and carbon dioxide storage, are added to further reduce the emissions. The effects on energy and the environment and the costs of the policy packages have been calculated by the Netherlands Energy Research Foundation (ECN). Those figures served as input for the CPB-calculations with the multi-sectoral model Athena. In variant 1 the volume of private consumption (an indicator for the material welfare loss) is, in 2020, 1.5% lower in comparison with the baseline scenario. GDP diminishes with 1 % and labour demand is 0.5% lower. As a consequence of the gradually increasing government subsidies to finance the extra costs of environmental investments and backstop-options the negative effects are increasing gradually too. This process will continue also after 2020 because the subsidies will be still growing after the scenario period. The negative effects of variant 2 in 2020 are about 50% higher than the results for variant 1. Private consumption decreases with 2.5%, GDP is 1.75% lower and employment diminishes with 0.75%. More subsidies for backstop-options, a higher increase of the small-user energy tax and a less positive effect because of less environmental investments, particularly less investments in dwellings, account for the more negative picture in comparison with the results for variant 1. The study ends with some points of discussion as

  7. Discovery of rare variants via sequencing: implications for the design of complex trait association studies.

    Directory of Open Access Journals (Sweden)

    Bingshan Li

    2009-05-01

    Full Text Available There is strong evidence that rare variants are involved in complex disease etiology. The first step in implicating rare variants in disease etiology is their identification through sequencing in both randomly ascertained samples (e.g., the 1,000 Genomes Project and samples ascertained according to disease status. We investigated to what extent rare variants will be observed across the genome and in candidate genes in randomly ascertained samples, the magnitude of variant enrichment in diseased individuals, and biases that can occur due to how variants are discovered. Although sequencing cases can enrich for casual variants, when a gene or genes are not involved in disease etiology, limiting variant discovery to cases can lead to association studies with dramatically inflated false positive rates.

  8. BRCA2 hypomorphic missense variants confer moderate risks of breast cancer

    OpenAIRE

    Shimelis, Hermela; Mesman, Romy L.s.; Von Nicolai, Catharina; Ehlen, Asa; Guidugli, Lucia; Martin, Charlotte; Calleja, Fabienne Mgr; Meeks, Huong; Hallberg, Emily; Hinton, Jamie; Lilyquist, Jenna; Hu, Chunling; Aalfs, Cora M; Aittomaki, Kristiina; Andrulis, Irene L.

    2017-01-01

    Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case–control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ances...

  9. Whole-genome sequencing and genetic variant analysis of a Quarter Horse mare.

    KAUST Repository

    Doan, Ryan; Cohen, Noah D; Sawyer, Jason; Ghaffari, Noushin; Johnson, Charlie D; Dindot, Scott V

    2012-01-01

    BACKGROUND: The catalog of genetic variants in the horse genome originates from a few select animals, the majority originating from the Thoroughbred mare used for the equine genome sequencing project. The purpose of this study was to identify genetic variants, including single nucleotide polymorphisms (SNPs), insertion/deletion polymorphisms (INDELs), and copy number variants (CNVs) in the genome of an individual Quarter Horse mare sequenced by next-generation sequencing. RESULTS: Using massively parallel paired-end sequencing, we generated 59.6 Gb of DNA sequence from a Quarter Horse mare resulting in an average of 24.7X sequence coverage. Reads were mapped to approximately 97% of the reference Thoroughbred genome. Unmapped reads were de novo assembled resulting in 19.1 Mb of new genomic sequence in the horse. Using a stringent filtering method, we identified 3.1 million SNPs, 193 thousand INDELs, and 282 CNVs. Genetic variants were annotated to determine their impact on gene structure and function. Additionally, we genotyped this Quarter Horse for mutations of known diseases and for variants associated with particular traits. Functional clustering analysis of genetic variants revealed that most of the genetic variation in the horse's genome was enriched in sensory perception, signal transduction, and immunity and defense pathways. CONCLUSIONS: This is the first sequencing of a horse genome by next-generation sequencing and the first genomic sequence of an individual Quarter Horse mare. We have increased the catalog of genetic variants for use in equine genomics by the addition of novel SNPs, INDELs, and CNVs. The genetic variants described here will be a useful resource for future studies of genetic variation regulating performance traits and diseases in equids.

  10. Germline contamination and leakage in whole genome somatic single nucleotide variant detection.

    Science.gov (United States)

    Sendorek, Dorota H; Caloian, Cristian; Ellrott, Kyle; Bare, J Christopher; Yamaguchi, Takafumi N; Ewing, Adam D; Houlahan, Kathleen E; Norman, Thea C; Margolin, Adam A; Stuart, Joshua M; Boutros, Paul C

    2018-01-31

    The clinical sequencing of cancer genomes to personalize therapy is becoming routine across the world. However, concerns over patient re-identification from these data lead to questions about how tightly access should be controlled. It is not thought to be possible to re-identify patients from somatic variant data. However, somatic variant detection pipelines can mistakenly identify germline variants as somatic ones, a process called "germline leakage". The rate of germline leakage across different somatic variant detection pipelines is not well-understood, and it is uncertain whether or not somatic variant calls should be considered re-identifiable. To fill this gap, we quantified germline leakage across 259 sets of whole-genome somatic single nucleotide variant (SNVs) predictions made by 21 teams as part of the ICGC-TCGA DREAM Somatic Mutation Calling Challenge. The median somatic SNV prediction set contained 4325 somatic SNVs and leaked one germline polymorphism. The level of germline leakage was inversely correlated with somatic SNV prediction accuracy and positively correlated with the amount of infiltrating normal cells. The specific germline variants leaked differed by tumour and algorithm. To aid in quantitation and correction of leakage, we created a tool, called GermlineFilter, for use in public-facing somatic SNV databases. The potential for patient re-identification from leaked germline variants in somatic SNV predictions has led to divergent open data access policies, based on different assessments of the risks. Indeed, a single, well-publicized re-identification event could reshape public perceptions of the values of genomic data sharing. We find that modern somatic SNV prediction pipelines have low germline-leakage rates, which can be further reduced, especially for cloud-sharing, using pre-filtering software.

  11. Whole-genome sequencing and genetic variant analysis of a Quarter Horse mare.

    KAUST Repository

    Doan, Ryan

    2012-02-17

    BACKGROUND: The catalog of genetic variants in the horse genome originates from a few select animals, the majority originating from the Thoroughbred mare used for the equine genome sequencing project. The purpose of this study was to identify genetic variants, including single nucleotide polymorphisms (SNPs), insertion/deletion polymorphisms (INDELs), and copy number variants (CNVs) in the genome of an individual Quarter Horse mare sequenced by next-generation sequencing. RESULTS: Using massively parallel paired-end sequencing, we generated 59.6 Gb of DNA sequence from a Quarter Horse mare resulting in an average of 24.7X sequence coverage. Reads were mapped to approximately 97% of the reference Thoroughbred genome. Unmapped reads were de novo assembled resulting in 19.1 Mb of new genomic sequence in the horse. Using a stringent filtering method, we identified 3.1 million SNPs, 193 thousand INDELs, and 282 CNVs. Genetic variants were annotated to determine their impact on gene structure and function. Additionally, we genotyped this Quarter Horse for mutations of known diseases and for variants associated with particular traits. Functional clustering analysis of genetic variants revealed that most of the genetic variation in the horse\\'s genome was enriched in sensory perception, signal transduction, and immunity and defense pathways. CONCLUSIONS: This is the first sequencing of a horse genome by next-generation sequencing and the first genomic sequence of an individual Quarter Horse mare. We have increased the catalog of genetic variants for use in equine genomics by the addition of novel SNPs, INDELs, and CNVs. The genetic variants described here will be a useful resource for future studies of genetic variation regulating performance traits and diseases in equids.

  12. A review of variant hemoglobins interfering with hemoglobin A1c measurement.

    Science.gov (United States)

    Little, Randie R; Roberts, William L

    2009-05-01

    Hemoglobin A1c (HbA1c) is used routinely to monitor long-term glycemic control in people with diabetes mellitus, as HbA1c is related directly to risks for diabetic complications. The accuracy of HbA1c methods can be affected adversely by the presence of hemoglobin (Hb) variants or elevated levels of fetal hemoglobin (HbF). The effect of each variant or elevated HbF must be examined with each specific method. The most common Hb variants worldwide are HbS, HbE, HbC, and HbD. All of these Hb variants have single amino acid substitutions in the Hb beta chain. HbF is the major hemoglobin during intrauterine life; by the end of the first year, HbF falls to values close to adult levels of approximately 1%. However, elevated HbF levels can occur in certain pathologic conditions or with hereditary persistence of fetal hemoglobin. In a series of publications over the past several years, the effects of these four most common Hb variants and elevated HbF have been described. There are clinically significant interferences with some methods for each of these variants. A summary is given showing which methods are affected by the presence of the heterozygous variants S, E, C, and D and elevated HbF. Methods are divided by type (immunoassay, ion-exchange high-performance liquid chromatography, boronate affinity, other) with an indication of whether the result is artificially increased or decreased by the presence of a Hb variant. Laboratorians should be aware of the limitations of their method with respect to these interferences. 2009 Diabetes Technology Society.

  13. Compositions and methods comprising cellulase variants with reduced affinity to non-cellulosic materials

    Energy Technology Data Exchange (ETDEWEB)

    Cascao-Pereira, Luis; Kaper, Thijs; Kelemen, Bradley R.; Liu, Amy D.

    2017-07-04

    The present disclosure relates to cellulase variants. In particular the present disclosure relates to cellulase variants having reduced binding to non-cellulosic materials. Also described are nucleic acids encoding the cellulase, compositions comprising said cellulase, methods of identifying cellulose variants and methods of using the compositions.

  14. Compositions and methods comprising cellulase variants with reduced affinity to non-cellulosic materials

    Science.gov (United States)

    Cascao-Pereira, Luis G.; Kaper, Thijs; Kelemen, Bradley R; Liu, Amy D.

    2012-08-07

    The present disclosure relates to cellulase variants. In particular the present disclosure relates to cellulase variants having reduced binding to non-cellulosic materials. Also described are nucleic acids encoding the cellulase, compositions comprising said cellulase, methods of identifying cellulose variants and methods of using the compositions.

  15. Compositions and methods comprising cellulase variants with reduced affinity to non-cellulosic materials

    Energy Technology Data Exchange (ETDEWEB)

    Cascao-Pereira, Luis G; Kaper, Thijs; Kelemen, Bradley R; Liu, Amy D

    2015-04-07

    The present disclosure relates to cellulase variants. In particular the present disclosure relates to cellulase variants having reduced binding to non-cellulosic materials. Also described are nucleic acids encoding the cellulase, compositions comprising said cellulase, methods of identifying cellulose variants and methods of using the compositions.

  16. Spatially variant periodic structures in electromagnetics

    Science.gov (United States)

    Rumpf, Raymond C.; Pazos, Javier J.; Digaum, Jennefir L.; Kuebler, Stephen M.

    2015-01-01

    Spatial transforms are a popular technique for designing periodic structures that are macroscopically inhomogeneous. The structures are often required to be anisotropic, provide a magnetic response, and to have extreme values for the constitutive parameters in Maxwell's equations. Metamaterials and photonic crystals are capable of providing these, although sometimes only approximately. The problem still remains about how to generate the geometry of the final lattice when it is functionally graded, or spatially varied. This paper describes a simple numerical technique to spatially vary any periodic structure while minimizing deformations to the unit cells that would weaken or destroy the electromagnetic properties. New developments in this algorithm are disclosed that increase efficiency, improve the quality of the lattices and provide the ability to design aplanatic metasurfaces. The ability to spatially vary a lattice in this manner enables new design paradigms that are not possible using spatial transforms, three of which are discussed here. First, spatially variant self-collimating photonic crystals are shown to flow unguided waves around very tight bends using ordinary materials with low refractive index. Second, multi-mode waveguides in spatially variant band gap materials are shown to guide waves around bends without mixing power between the modes. Third, spatially variant anisotropic materials are shown to sculpt the near-field around electric components. This can be used to improve electromagnetic compatibility between components in close proximity. PMID:26217058

  17. pyAmpli: an amplicon-based variant filter pipeline for targeted resequencing data.

    Science.gov (United States)

    Beyens, Matthias; Boeckx, Nele; Van Camp, Guy; Op de Beeck, Ken; Vandeweyer, Geert

    2017-12-14

    Haloplex targeted resequencing is a popular method to analyze both germline and somatic variants in gene panels. However, involved wet-lab procedures may introduce false positives that need to be considered in subsequent data-analysis. No variant filtering rationale addressing amplicon enrichment related systematic errors, in the form of an all-in-one package, exists to our knowledge. We present pyAmpli, a platform independent parallelized Python package that implements an amplicon-based germline and somatic variant filtering strategy for Haloplex data. pyAmpli can filter variants for systematic errors by user pre-defined criteria. We show that pyAmpli significantly increases specificity, without reducing sensitivity, essential for reporting true positive clinical relevant mutations in gene panel data. pyAmpli is an easy-to-use software tool which increases the true positive variant call rate in targeted resequencing data. It specifically reduces errors related to PCR-based enrichment of targeted regions.

  18. Gender-oriented Commonalities among Canadian and Iranian Englishes: An Analysis of Yes/No Question Variants

    Directory of Open Access Journals (Sweden)

    Laya Heidari Darani

    2010-05-01

    Full Text Available This study investigatesvariability in English yes/no questions as well as the commonalities among yes/no question variants produced by members of two different varieties of English: Canadian English native speakers and Iranian EFL learners.Further, it probes the role of gender in theEnglish yes/no question variants produced by Canadian English native speakers and those produced by Iranian EFL learners. A modified version of the Edinburgh Map Task was used in data collection. 60 Canadians and Iranians performed the task and made English yes/no question variants considering the informal context. Based on the results, the same types of yes/no question variants were produced by both groups. However, with respect to quantity, Canadians made more variants while the context of use was similar. Another difference noticed was the most frequent variant: Iranians’ frequent variant coincided with the informal context, yet the Canadians’ frequent variant did not. Regarding gender, Iranians did not produce any gender-based variant; while Canadians showed that their production of yes/no question variants was gender-oriented. These findings revealed that both Canadians and Iranians from two different varieties of English syntactically behaved similarly, but their sociolinguistic behavior was not the same.

  19. Microstructure evolution to reach the single variant in an ordered Fe–55at.%Pd alloy

    International Nuclear Information System (INIS)

    Farjami, Sahar; Fukuda, Takashi; Kakeshita, Tomoyuki

    2013-01-01

    Highlights: ► We confirmed formation of the single variant in Fe–55at.%Pd by XRD measurement and TEM observation. ► The size of each ordered domain is about 2 nm at the early stage of ordering. ► High density of antiphase boundaries has been observed after formation of the single variant. -- Abstract: Recently, we reported single variant formation in an Fe–55at.%Pd is certainly realized from a disordered fcc-phase to an ordered L1 0 -phase by heat-treatment under magnetic field. In the present study, we have investigated microstructure evolution during the process of the single variant formation by an X-ray diffraction and an electron microscopy observation. As a result, followings are obtained: size of the ordered particles at the early stage of ordering is about 2 nm and the nucleation ratio of preferable variant, whose easy axis lies in the field direction, is higher than that of other variants. Each of the ordered preferable variant grows by consuming the order variants and finally come together to become a single variant. Based on the observation, a model is proposed for the single variant formation of the ordered L1 0 -phase under magnetic field

  20. Rare and low-frequency coding variants alter human adult height

    NARCIS (Netherlands)

    Marouli, Eirini; Graff, Mariaelisa; Medina-Gomez, Carolina; Lo, Ken Sin; Wood, Andrew R.; Kjaer, Troels R.; Fine, Rebecca S.; Lu, Yingchang; Schurmann, Claudia; Highland, Heather M.; Rüeger, Sina; Thorleifsson, Gudmar; Justice, Anne E.; Lamparter, David; Stirrups, Kathleen E.; Turcot, Valérie; Young, Kristin L.; Winkler, Thomas W.; Esko, Tõnu; Karaderi, Tugce; Locke, Adam E.; Masca, Nicholas G. D.; Ng, Maggie C. Y.; Mudgal, Poorva; Rivas, Manuel A.; Vedantam, Sailaja; Mahajan, Anubha; Guo, Xiuqing; Abecasis, Goncalo; Aben, Katja K.; Adair, Linda S.; Alam, Dewan S.; Albrecht, Eva; Allin, Kristine H.; Allison, Matthew; Amouyel, Philippe; Appel, Emil V.; Arveiler, Dominique; Asselbergs, Folkert W.; Auer, Paul L.; Balkau, Beverley; Banas, Bernhard; Bang, Lia E.; Benn, Marianne; Bergmann, Sven; Bielak, Lawrence F.; Blüher, Matthias; Boeing, Heiner; Boerwinkle, Eric; Böger, Carsten A.; Bonnycastle, Lori L.; Bork-Jensen, Jette; Bots, Michiel L.; Bottinger, Erwin P.; Bowden, Donald W.; Brandslund, Ivan; Breen, Gerome; Brilliant, Murray H.; Broer, Linda; Burt, Amber A.; Butterworth, Adam S.; Carey, David J.; Caulfield, Mark J.; Chambers, John C.; Chasman, Daniel I.; Chen, Yii-Der Ida; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y.; Cocca, Massimiliano; Collins, Francis S.; Cook, James P.; Corley, Janie; Galbany, Jordi Corominas; Cox, Amanda J.; Cuellar-Partida, Gabriel; Danesh, John; Davies, Gail; de Bakker, Paul I. W.; de Borst, Gert J.; de Denus, Simon; de Groot, Mark C. H.; de Mutsert, Renée; Deary, Ian J.; Dedoussis, George; Demerath, Ellen W.; den Hollander, Anneke I.; Dennis, Joe G.; Di Angelantonio, Emanuele; Drenos, Fotios; Du, Mengmeng; Dunning, Alison M.; Easton, Douglas F.; Ebeling, Tapani; Edwards, Todd L.; Ellinor, Patrick T.; Elliott, Paul; Evangelou, Evangelos; Farmaki, Aliki-Eleni; Faul, Jessica D.; Feitosa, Mary F.; Feng, Shuang; Ferrannini, Ele; Ferrario, Marco M.; Ferrieres, Jean; Florez, Jose C.; Ford, Ian; Fornage, Myriam; Franks, Paul W.; Frikke-Schmidt, Ruth; Galesloot, Tessel E.; Gan, Wei; Gandin, Ilaria; Gasparini, Paolo; Giedraitis, Vilmantas; Giri, Ayush; Girotto, Giorgia; Gordon, Scott D.; Gordon-Larsen, Penny; Gorski, Mathias; Grarup, Niels; Grove, Megan L.; Gudnason, Vilmundur; Gustafsson, Stefan; Hansen, Torben; Harris, Kathleen Mullan; Harris, Tamara B.; Hattersley, Andrew T.; Hayward, Caroline; He, Liang; Heid, Iris M.; Heikkilä, Kauko; Helgeland, Øyvind; Hernesniemi, Jussi; Hewitt, Alex W.; Hocking, Lynne J.; Hollensted, Mette; Holmen, Oddgeir L.; Hovingh, G. Kees; Howson, Joanna M. M.; Hoyng, Carel B.; Huang, Paul L.; Hveem, Kristian; Ikram, M. Arfan; Ingelsson, Erik; Jackson, Anne U.; Jansson, Jan-Håkan; Jarvik, Gail P.; Jensen, Gorm B.; Jhun, Min A.; Jia, Yucheng; Jiang, Xuejuan; Johansson, Stefan; Jørgensen, Marit E.; Jørgensen, Torben; Jousilahti, Pekka; Jukema, J. Wouter; Kahali, Bratati; Kahn, René S.; Kähönen, Mika; Kamstrup, Pia R.; Kanoni, Stavroula; Kaprio, Jaakko; Karaleftheri, Maria; Kardia, Sharon L. R.; Karpe, Fredrik; Kee, Frank; Keeman, Renske; Kiemeney, Lambertus A.; Kitajima, Hidetoshi; Kluivers, Kirsten B.; Kocher, Thomas; Komulainen, Pirjo; Kontto, Jukka; Kooner, Jaspal S.; Kooperberg, Charles; Kovacs, Peter; Kriebel, Jennifer; Kuivaniemi, Helena; Küry, Sébastien; Kuusisto, Johanna; La Bianca, Martina; Laakso, Markku; Lakka, Timo A.; Lange, Ethan M.; Lange, Leslie A.; Langefeld, Carl D.; Langenberg, Claudia; Larson, Eric B.; Lee, I.-Te; Lehtimäki, Terho; Lewis, Cora E.; Li, Huaixing; Li, Jin; Li-Gao, Ruifang; Lin, Honghuang; Lin, Li-An; Lin, Xu; Lind, Lars; Lindström, Jaana; Linneberg, Allan; Liu, Yeheng; Liu, Yongmei; Lophatananon, Artitaya; Luan, Jian'an; Lubitz, Steven A.; Lyytikäinen, Leo-Pekka; Mackey, David A.; Madden, Pamela A. F.; Manning, Alisa K.; Männistö, Satu; Marenne, Gaëlle; Marten, Jonathan; Martin, Nicholas G.; Mazul, Angela L.; Meidtner, Karina; Metspalu, Andres; Mitchell, Paul; Mohlke, Karen L.; Mook-Kanamori, Dennis O.; Morgan, Anna; Morris, Andrew D.; Morris, Andrew P.; Müller-Nurasyid, Martina; Munroe, Patricia B.; Nalls, Mike A.; Nauck, Matthias; Nelson, Christopher P.; Neville, Matt; Nielsen, Sune F.; Nikus, Kjell; Njølstad, Pål R.; Nordestgaard, Børge G.; Ntalla, Ioanna; O'Connel, Jeffrey R.; Oksa, Heikki; Loohuis, Loes M. Olde; Ophoff, Roel A.; Owen, Katharine R.; Packard, Chris J.; Padmanabhan, Sandosh; Palmer, Colin N. A.; Pasterkamp, Gerard; Patel, Aniruddh P.; Pattie, Alison; Pedersen, Oluf; Peissig, Peggy L.; Peloso, Gina M.; Pennell, Craig E.; Perola, Markus; Perry, James A.; Perry, John R. B.; Person, Thomas N.; Pirie, Ailith; Polasek, Ozren; Posthuma, Danielle; Raitakari, Olli T.; Rasheed, Asif; Rauramaa, Rainer; Reilly, Dermot F.; Reiner, Alex P.; Renström, Frida; Ridker, Paul M.; Rioux, John D.; Robertson, Neil; Robino, Antonietta; Rolandsson, Olov; Rudan, Igor; Ruth, Katherine S.; Saleheen, Danish; Salomaa, Veikko; Samani, Nilesh J.; Sandow, Kevin; Sapkota, Yadav; Sattar, Naveed; Schmidt, Marjanka K.; Schreiner, Pamela J.; Schulze, Matthias B.; Scott, Robert A.; Segura-Lepe, Marcelo P.; Shah, Svati; Sim, Xueling; Sivapalaratnam, Suthesh; Small, Kerrin S.; Smith, Albert Vernon; Smith, Jennifer A.; Southam, Lorraine; Spector, Timothy D.; Speliotes, Elizabeth K.; Starr, John M.; Steinthorsdottir, Valgerdur; Stringham, Heather M.; Stumvoll, Michael; Surendran, Praveen; 't Hart, Leen M.; Tansey, Katherine E.; Tardif, Jean-Claude; Taylor, Kent D.; Teumer, Alexander; Thompson, Deborah J.; Thorsteinsdottir, Unnur; Thuesen, Betina H.; Tönjes, Anke; Tromp, Gerard; Trompet, Stella; Tsafantakis, Emmanouil; Tuomilehto, Jaakko; Tybjaerg-Hansen, Anne; Tyrer, Jonathan P.; Uher, Rudolf; Uitterlinden, André G.; Ulivi, Sheila; van der Laan, Sander W.; van der Leij, Andries R.; van Duijn, Cornelia M.; van Schoor, Natasja M.; van Setten, Jessica; Varbo, Anette; Varga, Tibor V.; Varma, Rohit; Edwards, Digna R. Velez; Vermeulen, Sita H.; Vestergaard, Henrik; Vitart, Veronique; Vogt, Thomas F.; Vozzi, Diego; Walker, Mark; Wang, Feijie; Wang, Carol A.; Wang, Shuai; Wang, Yiqin; Wareham, Nicholas J.; Warren, Helen R.; Wessel, Jennifer; Willems, Sara M.; Wilson, James G.; Witte, Daniel R.; Woods, Michael O.; Wu, Ying; Yaghootkar, Hanieh; Yao, Jie; Yao, Pang; Yerges-Armstrong, Laura M.; Young, Robin; Zeggini, Eleftheria; Zhan, Xiaowei; Zhang, Weihua; Zhao, Jing Hua; Zhao, Wei; Zheng, He; Zhou, Wei; Rotter, Jerome I.; Boehnke, Michael; Kathiresan, Sekar; McCarthy, Mark I.; Willer, Cristen J.; Stefansson, Kari; Borecki, Ingrid B.; Liu, Dajiang J.; North, Kari E.; Heard-Costa, Nancy L.; Pers, Tune H.; Lindgren, Cecilia M.; Oxvig, Claus; Kutalik, Zoltán; Rivadeneira, Fernando; Loos, Ruth J. F.; Frayling, Timothy M.; Hirschhorn, Joel N.; Deloukas, Panos; Lettre, Guillaume

    2017-01-01

    Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to

  1. Runs of homozygosity and distribution of functional variants in cattle genome

    DEFF Research Database (Denmark)

    Zhang, Qianqian; Guldbrandtsen, Bernt; Bosse, Mirte

    Runs of homozygosity (ROH) are identified in four dairy cattle breeds using NGS data. Cattle populations have been exposed to strong artificial selection for some generations. Genomic regions under selection will show increased levels of ROH. By investigating the relationship between ROH and dist......Runs of homozygosity (ROH) are identified in four dairy cattle breeds using NGS data. Cattle populations have been exposed to strong artificial selection for some generations. Genomic regions under selection will show increased levels of ROH. By investigating the relationship between ROH...... and distribution of predicted deleterious and tolerated variants, we can gain insight into how selection shapes the distribution of functional variants in inbred regions. We observe that predicted deleterious variants are more enriched in ROHs than predicted tolerated variants. Moreover, increase of enrichment...

  2. Screening of whole genome sequences identified high-impact variants for stallion fertility.

    Science.gov (United States)

    Schrimpf, Rahel; Gottschalk, Maren; Metzger, Julia; Martinsson, Gunilla; Sieme, Harald; Distl, Ottmar

    2016-04-14

    Stallion fertility is an economically important trait due to the increase of artificial insemination in horses. The availability of whole genome sequence data facilitates identification of rare high-impact variants contributing to stallion fertility. The aim of our study was to genotype rare high-impact variants retrieved from next-generation sequencing (NGS)-data of 11 horses in order to unravel harmful genetic variants in large samples of stallions. Gene ontology (GO) terms and search results from public databases were used to obtain a comprehensive list of human und mice genes predicted to participate in the regulation of male reproduction. The corresponding equine orthologous genes were searched in whole genome sequence data of seven stallions and four mares and filtered for high-impact genetic variants using SnpEFF, SIFT and Polyphen 2 software. All genetic variants with the missing homozygous mutant genotype were genotyped on 337 fertile stallions of 19 breeds using KASP genotyping assays or PCR-RFLP. Mixed linear model analysis was employed for an association analysis with de-regressed estimated breeding values of the paternal component of the pregnancy rate per estrus (EBV-PAT). We screened next generation sequenced data of whole genomes from 11 horses for equine genetic variants in 1194 human and mice genes involved in male fertility and linked through common gene ontology (GO) with male reproductive processes. Variants were filtered for high-impact on protein structure and validated through SIFT and Polyphen 2. Only those genetic variants were followed up when the homozygote mutant genotype was missing in the detection sample comprising 11 horses. After this filtering process, 17 single nucleotide polymorphism (SNPs) were left. These SNPs were genotyped in 337 fertile stallions of 19 breeds using KASP genotyping assays or PCR-RFLP. An association analysis in 216 Hanoverian stallions revealed a significant association of the splice-site disruption variant

  3. Quantifying evolutionary dynamics from variant-frequency time series

    Science.gov (United States)

    Khatri, Bhavin S.

    2016-09-01

    From Kimura’s neutral theory of protein evolution to Hubbell’s neutral theory of biodiversity, quantifying the relative importance of neutrality versus selection has long been a basic question in evolutionary biology and ecology. With deep sequencing technologies, this question is taking on a new form: given a time-series of the frequency of different variants in a population, what is the likelihood that the observation has arisen due to selection or neutrality? To tackle the 2-variant case, we exploit Fisher’s angular transformation, which despite being discovered by Ronald Fisher a century ago, has remained an intellectual curiosity. We show together with a heuristic approach it provides a simple solution for the transition probability density at short times, including drift, selection and mutation. Our results show under that under strong selection and sufficiently frequent sampling these evolutionary parameters can be accurately determined from simulation data and so they provide a theoretical basis for techniques to detect selection from variant or polymorphism frequency time-series.

  4. Enrichment of deleterious variants of mitochondrial DNA polymerase gene (POLG1) in bipolar disorder.

    Science.gov (United States)

    Kasahara, Takaoki; Ishiwata, Mizuho; Kakiuchi, Chihiro; Fuke, Satoshi; Iwata, Nakao; Ozaki, Norio; Kunugi, Hiroshi; Minabe, Yoshio; Nakamura, Kazuhiko; Iwata, Yasuhide; Fujii, Kumiko; Kanba, Shigenobu; Ujike, Hiroshi; Kusumi, Ichiro; Kataoka, Muneko; Matoba, Nana; Takata, Atsushi; Iwamoto, Kazuya; Yoshikawa, Takeo; Kato, Tadafumi

    2017-08-01

    Rare missense variants, which likely account for a substantial portion of the genetic 'dark matter' for a common complex disease, are challenging because the impacts of variants on disease development are difficult to substantiate. This study aimed to examine the impacts of amino acid substitution variants in the POLG1 found in bipolar disorder, as an example and proof of concept, in three different modalities of assessment: in silico predictions, in vitro biochemical assays, and clinical evaluation. We then tested whether deleterious variants in POLG1 contributed to the genetics of bipolar disorder. We searched for variants in the POLG1 gene in 796 Japanese patients with bipolar disorder and 767 controls and comprehensively investigated all 23 identified variants in the three modalities of assessment. POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders. The healthy control data from the Tohoku Medical Megabank Organization were also employed. Although the frequency of carriers of deleterious variants varied from one method to another, every assessment achieved the same conclusion that deleterious POLG1 variants were significantly enriched in the variants identified in patients with bipolar disorder compared to those in controls. Together with mitochondrial dysfunction in bipolar disorder, the present results suggested deleterious POLG1 variants as a credible risk for the multifactorial disease. © 2016 The Authors. Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.

  5. New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants

    DEFF Research Database (Denmark)

    Andreasen, Charlotte Hartig; Nielsen, Jonas B; Refsgaard, Lena

    2013-01-01

    Cardiomyopathies are a heterogeneous group of diseases with various etiologies. We focused on three genetically determined cardiomyopathies: hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Eighty-four genes have so far been associated with these card......Cardiomyopathies are a heterogeneous group of diseases with various etiologies. We focused on three genetically determined cardiomyopathies: hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Eighty-four genes have so far been associated...... with these cardiomyopathies, but the disease-causing effect of reported variants is often dubious. In order to identify possible false-positive variants, we investigated the prevalence of previously reported cardiomyopathy-associated variants in recently published exome data. We searched for reported missense and nonsense...... variants in the NHLBI-Go Exome Sequencing Project (ESP) containing exome data from 6500 individuals. In ESP, we identified 94 variants out of 687 (14%) variants previously associated with HCM, 58 out of 337 (17%) variants associated with DCM, and 38 variants out of 209 (18%) associated with ARVC...

  6. Computational Approach to Annotating Variants of Unknown Significance in Clinical Next Generation Sequencing.

    Science.gov (United States)

    Schulz, Wade L; Tormey, Christopher A; Torres, Richard

    2015-01-01

    Next generation sequencing (NGS) has become a common technology in the clinical laboratory, particularly for the analysis of malignant neoplasms. However, most mutations identified by NGS are variants of unknown clinical significance (VOUS). Although the approach to define these variants differs by institution, software algorithms that predict variant effect on protein function may be used. However, these algorithms commonly generate conflicting results, potentially adding uncertainty to interpretation. In this review, we examine several computational tools used to predict whether a variant has clinical significance. In addition to describing the role of these tools in clinical diagnostics, we assess their efficacy in analyzing known pathogenic and benign variants in hematologic malignancies. Copyright© by the American Society for Clinical Pathology (ASCP).

  7. Estimating the contribution of genetic variants to difference in incidence of disease between population groups

    Science.gov (United States)

    Moonesinghe, Ramal; Ioannidis, John PA; Flanders, W Dana; Yang, Quanhe; Truman, Benedict I; Khoury, Muin J

    2012-01-01

    Genome-wide association studies have identified multiple genetic susceptibility variants to several complex human diseases. However, risk-genotype frequency at loci showing robust associations might differ substantially among different populations. In this paper, we present methods to assess the contribution of genetic variants to the difference in the incidence of disease between different population groups for different scenarios. We derive expressions for the contribution of a single genetic variant, multiple genetic variants, and the contribution of the joint effect of a genetic variant and an environmental factor to the difference in the incidence of disease. The contribution of genetic variants to the difference in incidence increases with increasing difference in risk-genotype frequency, but declines with increasing difference in incidence between the two populations. The contribution of genetic variants also increases with increasing relative risk and the contribution of joint effect of genetic and environmental factors increases with increasing relative risk of the gene–environmental interaction. The contribution of genetic variants to the difference in incidence between two populations can be expressed as a function of the population attributable risks of the genetic variants in the two populations. The contribution of a group of genetic variants to the disparity in incidence of disease could change considerably by adding one more genetic variant to the group. Any estimate of genetic contribution to the disparity in incidence of disease between two populations at this stage seems to be an elusive goal. PMID:22333905

  8. Estimating the contribution of genetic variants to difference in incidence of disease between population groups.

    Science.gov (United States)

    Moonesinghe, Ramal; Ioannidis, John P A; Flanders, W Dana; Yang, Quanhe; Truman, Benedict I; Khoury, Muin J

    2012-08-01

    Genome-wide association studies have identified multiple genetic susceptibility variants to several complex human diseases. However, risk-genotype frequency at loci showing robust associations might differ substantially among different populations. In this paper, we present methods to assess the contribution of genetic variants to the difference in the incidence of disease between different population groups for different scenarios. We derive expressions for the contribution of a single genetic variant, multiple genetic variants, and the contribution of the joint effect of a genetic variant and an environmental factor to the difference in the incidence of disease. The contribution of genetic variants to the difference in incidence increases with increasing difference in risk-genotype frequency, but declines with increasing difference in incidence between the two populations. The contribution of genetic variants also increases with increasing relative risk and the contribution of joint effect of genetic and environmental factors increases with increasing relative risk of the gene-environmental interaction. The contribution of genetic variants to the difference in incidence between two populations can be expressed as a function of the population attributable risks of the genetic variants in the two populations. The contribution of a group of genetic variants to the disparity in incidence of disease could change considerably by adding one more genetic variant to the group. Any estimate of genetic contribution to the disparity in incidence of disease between two populations at this stage seems to be an elusive goal.

  9. MR imaging of the ankle: Normal variants

    International Nuclear Information System (INIS)

    Noto, A.M.; Cheung, Y.; Rosenberg, Z.S.; Norman, A.; Leeds, N.E.

    1987-01-01

    Thirty asymptomatic ankles were studied with high-resolution surface coil MR imaging. The thirty ankles were reviewed for identification or normal structures. The MR appearance of the deltoid and posterior to talo-fibular ligaments, peroneous brevis and longus tendons, and posterior aspect of the tibial-talar joint demonstrated several normal variants not previously described. These should not be misinterpreted as pathologic processes. The specific findings included (1) cortical irregularity of the posterior tibial-talar joint in 27 of 30 cases which should not be mistaken for osteonecrois; (2) normal posterior talo-fibular ligament with irregular and frayed inhomogeneity, which represents a normal variant in seven of ten cases; and (3) fluid in the shared peroneal tendons sheath which may be confused for a longitudinal tendon tear in three of 30 cases. Ankle imaging with the use of MR is still a relatively new procedure. Further investigation is needed to better define normal anatomy as well as normal variants. The authors described several structures that normally present with variable MR imaging appearances. This is clinically significant in order to maintain a high sensitivity and specificity in MR imaging interpretation

  10. Stability and function of interdomain linker variants of glucoamylase 1 from Aspergillus niger.

    Science.gov (United States)

    Sauer, J; Christensen, T; Frandsen, T P; Mirgorodskaya, E; McGuire, K A; Driguez, H; Roepstorff, P; Sigurskjold, B W; Svensson, B

    2001-08-07

    Several variants of glucoamylase 1 (GA1) from Aspergillus niger were created in which the highly O-glycosylated peptide (aa 468--508) connecting the (alpha/alpha)(6)-barrel catalytic domain and the starch binding domain was substituted at the gene level by equivalent segments of glucoamylases from Hormoconis resinae, Humicola grisea, and Rhizopus oryzae encoding 5, 19, and 36 amino acid residues. Variants were constructed in which the H. resinae linker was elongated by proline-rich sequences as this linker itself apparently was too short to allow formation of the corresponding protein variant. Size and isoelectric point of GA1 variants reflected differences in linker length, posttranslational modification, and net charge. While calculated polypeptide chain molecular masses for wild-type GA1, a nonnatural proline-rich linker variant, H. grisea, and R. oryzae linker variants were 65,784, 63,777, 63,912, and 65,614 Da, respectively, MALDI-TOF-MS gave values of 82,042, 73,800, 73,413, and 90,793 Da, respectively, where the latter value could partly be explained by an N-glycosylation site introduced near the linker C-terminus. The k(cat) and K(m) for hydrolysis of maltooligodextrins and soluble starch, and the rate of hydrolysis of barley starch granules were essentially the same for the variants as for wild-type GA1. beta-Cyclodextrin, acarbose, and two heterobidentate inhibitors were found by isothermal titration calorimetry to bind to the catalytic and starch binding domains of the linker variants, indicating that the function of the active site and the starch binding site was maintained. The stability of GA1 linker variants toward GdnHCl and heat, however, was reduced compared to wild-type.

  11. GCPII Variants, Paralogs and Orthologs

    Czech Academy of Sciences Publication Activity Database

    Hlouchová, Klára; Navrátil, Václav; Tykvart, Jan; Šácha, Pavel; Konvalinka, Jan

    2012-01-01

    Roč. 19, č. 9 (2012), s. 1316-1322 ISSN 0929-8673 R&D Projects: GA ČR GAP304/12/0847 Institutional research plan: CEZ:AV0Z40550506 Keywords : PSMA * GCPIII * NAALADase L * splice variants * homologs * PSMAL Subject RIV: CE - Biochemistry Impact factor: 4.070, year: 2012

  12. Contrasting roles of the ABCG2 Q141K variant in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Sobek, Kathryn M. [Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA (United States); Cummings, Jessica L. [Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA (United States); Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (United States); Bacich, Dean J. [Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA (United States); Department of Urology, University of Texas Health Science Center, San Antonio, TX (United States); O’Keefe, Denise S., E-mail: OKeefeD@uthscsa.edu [Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA (United States); Department of Urology, University of Texas Health Science Center, San Antonio, TX (United States)

    2017-05-01

    ABCG2 is a membrane transport protein that effluxes growth-promoting molecules, such as folates and dihydrotestosterone, as well as chemotherapeutic agents. Therefore it is important to determine how variants of ABCG2 affect the transporter function in order to determine whether modified treatment regimens may be necessary for patients harboring ABCG2 variants. Previous studies have demonstrated an association between the ABCG2 Q141K variant and overall survival after a prostate cancer diagnosis. We report here that in patients with recurrent prostate cancer, those who carry the ABCG2 Q141K variant had a significantly shorter time to PSA recurrence post-prostatectomy than patients homozygous for wild-type ABCG2 (P=0.01). Transport studies showed that wild-type ABCG2 was able to efflux more folic acid than the Q141K variant (P<0.002), suggesting that retained tumoral folate contributes to the decreased time to PSA recurrence in the Q141K variant patients. In a seemingly conflicting study, it was previously reported that docetaxel-treated Q141K variant prostate cancer patients have a longer survival time. We found this may be due to less efficient docetaxel efflux in cells with the Q141K variant versus wild-type ABCG2. In human prostate cancer tissues, confocal microscopy revealed that all genotypes had a mixture of cytoplasmic and plasma membrane staining, with noticeably less staining in the two homozygous KK patients. In conclusion, the Q141K variant plays contrasting roles in prostate cancer: 1) by decreasing folate efflux, increased intracellular folate levels result in enhanced tumor cell proliferation and therefore time to recurrence decreases; and 2) in patients treated with docetaxel, by decreasing its efflux, intratumoral docetaxel levels and tumor cell drug sensitivity increase and therefore patient survival time increases. Taken together, these data suggest that a patient's ABCG2 genotype may be important when determining a personalized treatment

  13. Influence of population diversity on neurovirulence potential of plaque purified L-Zagreb variants.

    Science.gov (United States)

    Ivancic-Jelecki, Jelena; Forcic, Dubravko; Jagusic, Maja; Kosutic-Gulija, Tanja; Mazuran, Renata; Balija, Maja Lang; Isakov, Ofer; Shomron, Noam

    2016-04-29

    Despite continuing research efforts, determinants of mumps virus virulence are still largely unknown. One of consequences of this is difficulty in striking a balance between efficacy and safety of live attenuated mumps vaccines. Among mumps vaccine strains associated with occurrence of postvaccinal aseptic meningitis is L-Zagreb, developed by further attenuation of vaccine strain L-3. Starting from an archived L-Zagreb sample with suboptimal neuroattenuation score, we isolated different viral variants and compared their genetic and phenotypic properties, in investigation of neurovirulence markers. Six different L-Zagreb variants were isolated by plaque purification. Their neurovirulent status was determined by rat-based neurovirulence test; population structure was determined by deep sequencing. We isolated one well neuroattenuated viral variant, two marginally neuroattenuated, and three insufficiently neuroattenuated. No genetic markers of neurovirulence could be identified. None of variants had detectable amounts of defective interfering particles. Two characteristics set insufficiently neuroattenuated variants apart from less-neurovirulent ones: elevated variability level in regions 1293-3314, 5363-7773 and 9382-11657, and/or elevated number of mutations present in frequencies ≥ 1%. The most neurovirulent variants possessed both of these features. Distinctive heterogeneity profiles were obtained for insufficiently neuroattenuated L-Zagreb variants. No markers that would discriminate between marginally and well neuroattenuated variants were identified. The findings of this study may serve as a guideline during development of an improved L3/L-Zagreb vaccine strain. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Role of Androgen Receptor Variants in Prostate Cancer: Report from the 2017 Mission Androgen Receptor Variants Meeting.

    Science.gov (United States)

    Luo, Jun; Attard, Gerhardt; Balk, Steven P; Bevan, Charlotte; Burnstein, Kerry; Cato, Laura; Cherkasov, Artem; De Bono, Johann S; Dong, Yan; Gao, Allen C; Gleave, Martin; Heemers, Hannelore; Kanayama, Mayuko; Kittler, Ralf; Lang, Joshua M; Lee, Richard J; Logothetis, Christopher J; Matusik, Robert; Plymate, Stephen; Sawyers, Charles L; Selth, Luke A; Soule, Howard; Tilley, Wayne; Weigel, Nancy L; Zoubeidi, Amina; Dehm, Scott M; Raj, Ganesh V

    2018-05-01

    Although a number of studies have demonstrated the importance of constitutively active androgen receptor variants (AR-Vs) in prostate cancer, questions still remain about the precise role of AR-Vs in the progression of castration-resistant prostate cancer (CRPC). Key stakeholders and opinion leaders in prostate cancer convened on May 11, 2017 in Boston to establish the current state of the field of AR-Vs. The meeting "Mission Androgen Receptor Variants" was the second of its kind sponsored by the Prostate Cancer Foundation (PCF). This invitation-only event was attended by international leaders in the field and representatives from sponsoring organizations (PCF and industry sponsors). Eighteen faculty members gave short presentations, which were followed by in-depth discussions. Discussions focused on three thematic topics: (1) potential of AR-Vs as biomarkers of therapeutic resistance; (2) role of AR-Vs as functionally active CRPC progression drivers; and (3) utility of AR-Vs as therapeutic targets in CRPC. The three meeting organizers synthesized this meeting report, which is intended to summarize major data discussed at the meeting and identify key questions as well as strategies for addressing these questions. There was a critical consensus that further study of the AR-Vs is an important research focus in CRPC. Contrasting views and emphasis, each supported by data, were presented at the meeting, discussed among the participants, and synthesized in this report. This article highlights the state of knowledge and outlines the most pressing questions that need to be addressed to advance the AR-V field. Although further investigation is needed to delineate the role of androgen receptor (AR) variants in metastatic castration-resistant prostate cancer, advances in measurement science have enabled development of blood-based tests for treatment selection. Detection of AR variants (eg, AR-V7) identified a patient population with poor outcomes to existing AR

  15. Beyond the temporal pole: limbic memory circuit in the semantic variant of primary progressive aphasia.

    Science.gov (United States)

    Tan, Rachel H; Wong, Stephanie; Kril, Jillian J; Piguet, Olivier; Hornberger, Michael; Hodges, John R; Halliday, Glenda M

    2014-07-01

    Despite accruing evidence for relative preservation of episodic memory in the semantic variant of primary progressive aphasia (previously semantic dementia), the neural basis for this remains unclear, particularly in light of their well-established hippocampal involvement. We recently investigated the Papez network of memory structures across pathological subtypes of behavioural variant frontotemporal dementia and demonstrated severe degeneration of all relay nodes, with the anterior thalamus in particular emerging as crucial for intact episodic memory. The present study investigated the status of key components of Papez circuit (hippocampus, mammillary bodies, anterior thalamus, cingulate cortex) and anterior temporal cortex using volumetric and quantitative cell counting methods in pathologically-confirmed cases with semantic variant of primary progressive aphasia (n = 8; 61-83 years; three males), behavioural variant frontotemporal dementia with TDP pathology (n = 9; 53-82 years; six males) and healthy controls (n = 8, 50-86 years; four males). Behavioural variant frontotemporal dementia cases with TDP pathology were selected because of the association between the semantic variant of primary progressive aphasia and TDP pathology. Our findings revealed that the semantic variant of primary progressive aphasia and behavioural variant frontotemporal dementia show similar degrees of anterior thalamic atrophy. The mammillary bodies and hippocampal body and tail were preserved in the semantic variant of primary progressive aphasia but were significantly atrophic in behavioural variant frontotemporal dementia. Importantly, atrophy in the anterior thalamus and mild progressive atrophy in the body of the hippocampus emerged as the main memory circuit regions correlated with increasing dementia severity in the semantic variant of primary progressive aphasia. Quantitation of neuronal populations in the cingulate cortices confirmed the selective loss of anterior cingulate

  16. Performance of genotype imputation for low frequency and rare variants from the 1000 genomes.

    Science.gov (United States)

    Zheng, Hou-Feng; Rong, Jing-Jing; Liu, Ming; Han, Fang; Zhang, Xing-Wei; Richards, J Brent; Wang, Li

    2015-01-01

    Genotype imputation is now routinely applied in genome-wide association studies (GWAS) and meta-analyses. However, most of the imputations have been run using HapMap samples as reference, imputation of low frequency and rare variants (minor allele frequency (MAF) 1000 Genomes panel) are available to facilitate imputation of these variants. Therefore, in order to estimate the performance of low frequency and rare variants imputation, we imputed 153 individuals, each of whom had 3 different genotype array data including 317k, 610k and 1 million SNPs, to three different reference panels: the 1000 Genomes pilot March 2010 release (1KGpilot), the 1000 Genomes interim August 2010 release (1KGinterim), and the 1000 Genomes phase1 November 2010 and May 2011 release (1KGphase1) by using IMPUTE version 2. The differences between these three releases of the 1000 Genomes data are the sample size, ancestry diversity, number of variants and their frequency spectrum. We found that both reference panel and GWAS chip density affect the imputation of low frequency and rare variants. 1KGphase1 outperformed the other 2 panels, at higher concordance rate, higher proportion of well-imputed variants (info>0.4) and higher mean info score in each MAF bin. Similarly, 1M chip array outperformed 610K and 317K. However for very rare variants (MAF ≤ 0.3%), only 0-1% of the variants were well imputed. We conclude that the imputation of low frequency and rare variants improves with larger reference panels and higher density of genome-wide genotyping arrays. Yet, despite a large reference panel size and dense genotyping density, very rare variants remain difficult to impute.

  17. Variant selection of martensites in steel welded joints with low transformation temperature weld metals

    International Nuclear Information System (INIS)

    Takahashi, Masaru; Yasuda, Hiroyuki Y.

    2013-01-01

    Highlights: ► We examined the variant selection of martensites in the weld metals. ► We also measured the residual stress developed in the butt and box welded joints. ► 24 martensite variants were randomly selected in the butt welded joint. ► High tensile residual stress in the box welded joint led to the strong variant selection. ► We discussed the rule of the variant selection focusing on the residual stress. -- Abstract: Martensitic transformation behavior in steel welded joints with low transformation temperature weld (LTTW) metal was examined focusing on the variant selection of martensites. The butt and box welded joints were prepared with LTTW metals and 980 MPa grade high strength steels. The residual stress of the welded joints, which was measured by a neutron diffraction technique, was effectively reduced by the expansion of the LTTW metals by the martensitic transformation during cooling after the welding process. In the LTTW metals, the retained austenite and martensite phases have the Kurdjumov–Sachs (K–S) orientation relationship. The variant selection of the martensites in the LTTW metals depended strongly on the type of welded joints. In the butt welded joint, 24 K–S variants were almost randomly selected while a few variants were preferentially chosen in the box welded joint. This suggests that the high residual stress developed in the box welded joint accelerated the formation of specific variants during the cooling process, in contrast to the butt welded joint with low residual stress

  18. Screening the Biosphere: The Fungicolous Fungus Trichoderma phellinicola, a Prolific Source of Hypophellins, New 17-, 18-, 19-, and 20-Residue Peptaibiotics

    DEFF Research Database (Denmark)

    Röhrich, Christian René; Iversen, Anita; Jaklitsch, Walter Michael

    2013-01-01

    To investigate the significance of antibiotics for the producing organism(s) in the natural habitat, we screened a specimen of the fungicolous fungus Trichoderma phellinicola (syn. Hypocrea phellinicola) growing on its natural host Phellinus ferruginosus. Results revealed that a particular group...

  19. Trichoderma amazonicum, a new endophytic species on Hevea brasiliensis and H. guianensis from the Amazon basin

    Science.gov (United States)

    A new species of Trichoderma (teleomorph Hypocrea, Ascomycota, Sordariomycetes, Hypocreales, Hypocreaceae), T. amazonicum, endophytic on the living sapwood and leaves of Hevea spp. trees is described. Trichoderma amazonicum is distinguished from closely related species in the Harzianum clade (e.g. ...

  20. Behavioral and language variants of frontotemporal dementia: a review of key symptoms.

    Science.gov (United States)

    Laforce, Robert

    2013-12-01

    While recent advances in the development of neuroimaging and molecular biomarkers for studying neurodegenerative conditions have revolutionized the field, dementia remains a clinical diagnosis. No component of the diagnostic process is more crucial than obtaining a good history. Getting to know the first manifestations of the disease, tracking their evolution and functional impact, combined with a targeted neurological examination, further guides differential diagnosis. This paper summarizes the key symptoms of the behavioral and language variants of frontotemporal dementia. The behavioral variant of frontotemporal dementia (bvFTD) is characterized by severe changes in behavior and personality such as disinhibition, apathy, loss of empathy, or stereotypic behavior, leading to a loss of social competence. Executive functions are impaired, while memory and visuospatial skills are relatively better preserved. By contrast, the language variants or primary progressive aphasias (PPAs) are marked by prominent language disturbances that can be subclassified into a non-fluent/agrammatic variant (naPPA), a semantic variant (svPPA), and a logopenic variant (lvPPA). Although combined characterization of clinical, imaging, biological and genetic biomarkers is essential to establish a detailed diagnosis of such heterogeneous conditions, the author emphasizes the importance of accurate recognition of key symptoms that can lead to better identification of underlying neuropathology and appropriate treatment approaches.

  1. Common Genetic Variants Found in HLA and KIR Immune Genes in Autism Spectrum Disorder

    OpenAIRE

    Torres, Anthony R.; Sweeten, Thayne L.; Johnson, Randall C.; Odell, Dennis; Westover, Jonna B.; Bray-Ward, Patricia; Ward, David C.; Davies, Christopher J.; Thomas, Aaron J.; Croen, Lisa A.; Benson, Michael

    2016-01-01

    The common variant - common disease hypothesis was proposed to explain diseases with strong inheritance. This model suggests that a genetic disease is the result of the combination of several common genetic variants. Common genetic variants are described as a 5% frequency differential between diseased versus matched control populations. This theory was recently supported by an epidemiology paper stating that about 50% of genetic risk for autism resides in common variants. However, rare va...

  2. BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

    DEFF Research Database (Denmark)

    Shimelis, Hermela; Mesman, Romy L S; Von Nicolai, Catharina

    2017-01-01

    Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk ......, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR....... were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA...... of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant...

  3. The Role of Constitutional Copy Number Variants in Breast Cancer

    Science.gov (United States)

    Walker, Logan C.; Wiggins, George A.R.; Pearson, John F.

    2015-01-01

    Constitutional copy number variants (CNVs) include inherited and de novo deviations from a diploid state at a defined genomic region. These variants contribute significantly to genetic variation and disease in humans, including breast cancer susceptibility. Identification of genetic risk factors for breast cancer in recent years has been dominated by the use of genome-wide technologies, such as single nucleotide polymorphism (SNP)-arrays, with a significant focus on single nucleotide variants. To date, these large datasets have been underutilised for generating genome-wide CNV profiles despite offering a massive resource for assessing the contribution of these structural variants to breast cancer risk. Technical challenges remain in determining the location and distribution of CNVs across the human genome due to the accuracy of computational prediction algorithms and resolution of the array data. Moreover, better methods are required for interpreting the functional effect of newly discovered CNVs. In this review, we explore current and future application of SNP array technology to assess rare and common CNVs in association with breast cancer risk in humans. PMID:27600231

  4. Meta-analyses of HFE variants in coronary heart disease.

    Science.gov (United States)

    Lian, Jiangfang; Xu, Limin; Huang, Yi; Le, Yanping; Jiang, Danjie; Yang, Xi; Xu, Weifeng; Huang, Xiaoyan; Dong, Changzheng; Ye, Meng; Zhou, Jianqing; Duan, Shiwei

    2013-09-15

    HFE gene variants can cause hereditary hemochromatosis (HH) that often comes along with an increased risk of coronary heart disease (CHD). The goal of our study is to assess the contribution of four HFE gene variants to the risk of CHD. We conducted four meta-analyses of the studies examining the association between four HFE gene variants and the risk of CHD. A systematic search was conducted using MEDLINE, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI), Wanfang Chinese Periodical. Meta-analyses showed that HFE rs1799945-G allele was associated with a 6% increased risk of CHD (P=0.02, odds ratio (OR)=1.06, 95% confidence interval (CI)=1.01-1.11). However, no association between the other three HFE gene variants (rs1800562, rs1800730, and rs9366637) and CHD risk was observed by the meta-analyses (all P values>0.05). In addition, the results of our case-control study indicated that rs1800562 and rs1800730 were monomorphic, and that rs1799945 and rs9366637 were not associated with CHD in Han Chinese. Our meta-analysis suggested that a significant association existed between rs1799945 mutation and CHD, although this mutation was rare in Han Chinese. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. Impaired Interoceptive Accuracy in Semantic Variant Primary Progressive Aphasia

    Directory of Open Access Journals (Sweden)

    Charles R. Marshall

    2017-11-01

    Full Text Available BackgroundInteroception (the perception of internal bodily sensations is strongly linked to emotional experience and sensitivity to the emotions of others in healthy subjects. Interoceptive impairment may contribute to the profound socioemotional symptoms that characterize frontotemporal dementia (FTD syndromes, but remains poorly defined.MethodsPatients representing all major FTD syndromes and healthy age-matched controls performed a heartbeat counting task as a measure of interoceptive accuracy. In addition, patients had volumetric MRI for voxel-based morphometric analysis, and their caregivers completed a questionnaire assessing patients’ daily-life sensitivity to the emotions of others.ResultsInteroceptive accuracy was impaired in patients with semantic variant primary progressive aphasia relative to healthy age-matched individuals, but not in behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. Impaired interoceptive accuracy correlated with reduced daily-life emotional sensitivity across the patient cohort, and with atrophy of right insula, cingulate, and amygdala on voxel-based morphometry in the impaired semantic variant group, delineating a network previously shown to support interoceptive processing in the healthy brain.ConclusionInteroception is a promising novel paradigm for defining mechanisms of reduced emotional reactivity, empathy, and self-awareness in neurodegenerative syndromes and may yield objective measures for these complex symptoms.

  6. Functional analysis of four naturally occurring variants of human constitutive androstane receptor.

    Science.gov (United States)

    Ikeda, Shinobu; Kurose, Kouichi; Jinno, Hideto; Sai, Kimie; Ozawa, Shogo; Hasegawa, Ryuichi; Komamura, Kazuo; Kotake, Takeshi; Morishita, Hideki; Kamakura, Shiro; Kitakaze, Masafumi; Tomoike, Hitonobu; Tamura, Tomohide; Yamamoto, Noboru; Kunitoh, Hideo; Yamada, Yasuhide; Ohe, Yuichiro; Shimada, Yasuhiro; Shirao, Kuniaki; Kubota, Kaoru; Minami, Hironobu; Ohtsu, Atsushi; Yoshida, Teruhiko; Saijo, Nagahiro; Saito, Yoshiro; Sawada, Jun-ichi

    2005-01-01

    The human constitutive androstane receptor (CAR, NR1I3) is a member of the orphan nuclear receptor superfamily that plays an important role in the control of drug metabolism and disposition. In this study, we sequenced all the coding exons of the NR1I3 gene for 334 Japanese subjects. We identified three novel single nucleotide polymorphisms (SNPs) that induce non-synonymous alterations of amino acids (His246Arg, Leu308Pro, and Asn323Ser) residing in the ligand-binding domain of CAR, in addition to the Val133Gly variant, which was another CAR variant identified in our previous study. We performed functional analysis of these four naturally occurring CAR variants in COS-7 cells using a CYP3A4 promoter/enhancer reporter gene that includes the CAR responsive elements. The His246Arg variant caused marked reductions in both transactivation of the reporter gene and in the response to 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO), which is a human CAR-specific agonist. The transactivation ability of the Leu308Pro variant was also significantly decreased, but its responsiveness to CITCO was not abrogated. The transactivation ability and CITCO response of the Val133Gly and Asn323Ser variants did not change as compared to the wild-type CAR. These data suggest that the His246Arg and Leu308Pro variants, especially His246Arg, may influence the expression of drug-metabolizing enzymes and transporters that are transactivated by CAR.

  7. Arrhythmogenic KCNE gene variants: current knowledge and future challenges

    Directory of Open Access Journals (Sweden)

    Shawn M Crump

    2014-01-01

    Full Text Available There are twenty-five known inherited cardiac arrhythmia susceptibility genes, all of which encode either ion channel pore-forming subunits or proteins that regulate aspects of ion channel biology such as function, trafficking and localization. The human KCNE gene family comprises five potassium channel regulatory subunits, sequence variants in each of which are associated with cardiac arrhythmias. KCNE gene products exhibit promiscuous partnering and in some cases ubiquitous expression, hampering efforts to unequivocally correlate each gene to specific native potassium currents. Likewise, deducing the molecular etiology of cardiac arrhythmias in individuals harboring rare KCNE gene variants, or more common KCNE polymorphisms, can be challenging. In this review we provide an update on putative arrhythmia-causing KCNE gene variants, and discuss current thinking and future challenges in the study of molecular mechanisms of KCNE-associated cardiac rhythm disturbances.

  8. Antigenic variants of yellow fever virus with an altered neurovirulence phenotype in mice.

    Science.gov (United States)

    Ryman, K D; Xie, H; Ledger, T N; Campbell, G A; Barrett, A D

    1997-04-14

    The live-attenuated yellow fever (YF) vaccine virus, strain 17D-204, has long been known to consist of a heterologous population of virions. Gould et al. (J. Gen. Virol. 70, 1889-1894 (1989)) previously demonstrated that variant viruses exhibiting a YF wild-type-specific envelope (E) protein epitope are present at low frequency in the vaccine pool and were able to isolate representative virus variants with and without this epitope, designated 17D(+wt) and 17D(-wt), respectively. These variants were employed here in an investigation of YF virus pathogenesis in the mouse model. Both the 17D-204 parent and the 17D(+wt) variant viruses were lethal for adult outbred mice by the intracerebral route of inoculation. However, the 17D(-wt) variant was significantly attenuated (18% mortality rate) and replicated to much lower titer in the brains of infected mice. A single amino acid substitution in the envelope (E) protein at E-240 (Ala-->Val) was identified as responsible for the restricted replication of the 17D(-wt) variant in vivo. The 17D(+wt) variant has an additional second-site mutation, believed to encode a reversion to the neurovirulence phenotype of the 17D-204 parent virus. The amino acid substitution in the E protein at E-173 (Thr-->Ile) of the 17D(+wt) variant which results in the appearance of the wild-type-specific epitope or nucleotide changes in the 5' and 3' noncoding regions of the virus are proposed as a candidates.

  9. Comparison and evaluation of two exome capture kits and sequencing platforms for variant calling.

    Science.gov (United States)

    Zhang, Guoqiang; Wang, Jianfeng; Yang, Jin; Li, Wenjie; Deng, Yutian; Li, Jing; Huang, Jun; Hu, Songnian; Zhang, Bing

    2015-08-05

    To promote the clinical application of next-generation sequencing, it is important to obtain accurate and consistent variants of target genomic regions at low cost. Ion Proton, the latest updated semiconductor-based sequencing instrument from Life Technologies, is designed to provide investigators with an inexpensive platform for human whole exome sequencing that achieves a rapid turnaround time. However, few studies have comprehensively compared and evaluated the accuracy of variant calling between Ion Proton and Illumina sequencing platforms such as HiSeq 2000, which is the most popular sequencing platform for the human genome. The Ion Proton sequencer combined with the Ion TargetSeq Exome Enrichment Kit together make up TargetSeq-Proton, whereas SureSelect-Hiseq is based on the Agilent SureSelect Human All Exon v4 Kit and the HiSeq 2000 sequencer. Here, we sequenced exonic DNA from four human blood samples using both TargetSeq-Proton and SureSelect-HiSeq. We then called variants in the exonic regions that overlapped between the two exome capture kits (33.6 Mb). The rates of shared variant loci called by two sequencing platforms were from 68.0 to 75.3% in four samples, whereas the concordance of co-detected variant loci reached 99%. Sanger sequencing validation revealed that the validated rate of concordant single nucleotide polymorphisms (SNPs) (91.5%) was higher than the SNPs specific to TargetSeq-Proton (60.0%) or specific to SureSelect-HiSeq (88.3%). With regard to 1-bp small insertions and deletions (InDels), the Sanger sequencing validated rates of concordant variants (100.0%) and SureSelect-HiSeq-specific (89.6%) were higher than those of TargetSeq-Proton-specific (15.8%). In the sequencing of exonic regions, a combination of using of two sequencing strategies (SureSelect-HiSeq and TargetSeq-Proton) increased the variant calling specificity for concordant variant loci and the sensitivity for variant loci called by any one platform. However, for the

  10. Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease

    Directory of Open Access Journals (Sweden)

    Laura Ibanez

    2018-04-01

    Full Text Available Background: The prevalence of dementia in Parkinson disease (PD increases dramatically with advancing age, approaching 80% in patients who survive 20 years with the disease. Increasing evidence suggests clinical, pathological and genetic overlap between Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia with PD. However, the contribution of the dementia-causing genes to PD risk, cognitive impairment and dementia in PD is not fully established.Objective: To assess the contribution of coding variants in Mendelian dementia-causing genes on the risk of developing PD and the effect on cognitive performance of PD patients.Methods: We analyzed the coding regions of the amyloid-beta precursor protein (APP, Presenilin 1 and 2 (PSEN1, PSEN2, and Granulin (GRN genes from 1,374 PD cases and 973 controls using pooled-DNA targeted sequence, human exome-chip and whole-exome sequencing (WES data by single variant and gene base (SKAT-O and burden tests analyses. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE or the Montreal Cognitive Assessment (MoCA. The effect of coding variants in dementia-causing genes on cognitive performance was tested by multiple regression analysis adjusting for gender, disease duration, age at dementia assessment, study site and APOE carrier status.Results: Known AD pathogenic mutations in the PSEN1 (p.A79V and PSEN2 (p.V148I genes were found in 0.3% of all PD patients. There was a significant burden of rare, likely damaging variants in the GRN and PSEN1 genes in PD patients when compared with frequencies in the European population from the ExAC database. Multiple regression analysis revealed that PD patients carrying rare variants in the APP, PSEN1, PSEN2, and GRN genes exhibit lower cognitive tests scores than non-carrier PD patients (p = 2.0 × 10−4, independent of age at PD diagnosis, age at evaluation, APOE status or recruitment site.Conclusions: Pathogenic mutations in

  11. DaMold: A data-mining platform for variant annotation and visualization in molecular diagnostics research.

    Science.gov (United States)

    Pandey, Ram Vinay; Pabinger, Stephan; Kriegner, Albert; Weinhäusel, Andreas

    2017-07-01

    Next-generation sequencing (NGS) has become a powerful and efficient tool for routine mutation screening in clinical research. As each NGS test yields hundreds of variants, the current challenge is to meaningfully interpret the data and select potential candidates. Analyzing each variant while manually investigating several relevant databases to collect specific information is a cumbersome and time-consuming process, and it requires expertise and familiarity with these databases. Thus, a tool that can seamlessly annotate variants with clinically relevant databases under one common interface would be of great help for variant annotation, cross-referencing, and visualization. This tool would allow variants to be processed in an automated and high-throughput manner and facilitate the investigation of variants in several genome browsers. Several analysis tools are available for raw sequencing-read processing and variant identification, but an automated variant filtering, annotation, cross-referencing, and visualization tool is still lacking. To fulfill these requirements, we developed DaMold, a Web-based, user-friendly tool that can filter and annotate variants and can access and compile information from 37 resources. It is easy to use, provides flexible input options, and accepts variants from NGS and Sanger sequencing as well as hotspots in VCF and BED formats. DaMold is available as an online application at http://damold.platomics.com/index.html, and as a Docker container and virtual machine at https://sourceforge.net/projects/damold/. © 2017 Wiley Periodicals, Inc.

  12. [Approach to diagnosis and management of myeloproliferative neoplasm variants].

    Science.gov (United States)

    Mitsumori, Toru; Kirito, Keita

    2015-08-01

    Myeloproliferative neoplasm (MPN) variants are defined as relatively uncommon myeloid neoplasms which do not meet the criteria for either classical MPN or myelodysplastic syndrome. Due to the lack of specific markers, it has been challenging to accurately diagnose these malignant diseases. Recent studies have revealed new genetic abnormalities in MPN variants. These research advances are anticipated to open new approaches to not only achieving accurate diagnosis but also novel therapeutic options for these diseases.

  13. Hb variants in Korea: effect on HbA1c using five routine methods.

    Science.gov (United States)

    Yun, Yeo-Min; Ji, Misuk; Ko, Dae-Hyun; Chun, Sail; Kwon, Gye Cheol; Lee, Kyunghoon; Song, Sang Hoon; Seong, Moon Woo; Park, Sung Sup; Song, Junghan

    2017-07-26

    Quantification of glycated hemoglobin (HbA1c) is a challenge in patients with hemoglobin (Hb) variants. We evaluated the impact of various Hb variants on five routine HbA1c assays by comparing with the IFCC reference measurement procedure (RMP). Whole blood samples showing warning flags or no results on routine HPLC HbA1c assays were confirmed for Hb variants and were submitted to HbA1c quantification using Sebia Capillarys 2 Flex Piercing, Roche Tina-quant HbA1c Gen. 2, Bio-Rad Variant II Turbo 2.0, ADAMS HA-8180, Tosoh G8 standard mode, and IFCC RMP using LC-MS. Among 114 samples, the most common variants were Hb G-Coushatta (n=47), Queens (n=41), Ube-4 (n=11), Chad (n=4), Yamagata (n=4), G-His-Tsou (n=2), G-Taipei (n=1), Fort de France (n=1), Hoshida (n=1), and two novel variants (Hb α-globin, HBA 52 Gly>Cys and Hb β-globin, HBB 146 His>Asn). In terms of control samples, all the result of HbA1c were "acceptable", within the criteria of ±7% compared to IFCC RMP target values. However, percentage of "unacceptable" results of samples with Hb variants were 16% for Capillarys 2, 7% for Tina-quant, 51% for Variant II Turbo 2.0, 95% for G8 standard mode, and 89% for HA-8180. The Capillarys 2 and HA-8180 assay did not provide the results in 5 and 40 samples with Hb variants, respectively. HbA1c results from five routine assays in patients with relatively common Hb variants in Korea showed various degrees of bias compared to those of IFCC RMP. Therefore, laboratories should be aware of the limitation of their methods with respect to interference from Hb variants found commonly in their local population and suggest an alternative HbA1c quantification method.

  14. Development of industrial variant specification systems

    DEFF Research Database (Denmark)

    Hansen, Benjamin Loer

    be developed from a holistic and strategically anchored point of view. Another assumption is that this is a challenge for many industrial companies. Even though the literature presents many considerations on general issues covering new information technology, little work is found on the business perspectives...... are discussed. A list of structural variables and solution components has been created. These are related to four design aspects in the holistic system design covering the aspects of process design, selection of resources (such as hardware, software and humans), the design of information structures...... solution elements and structural variables to be used in the design of variant specification systems. The thesis presents a “top-down” procedure to be used to develop variant specification systems from a strategically anchored and holistic point of view. A methodology and related task variables...

  15. Modelling Product Families for Product Configuration Systems with Product Variant Master

    DEFF Research Database (Denmark)

    Mortensen, Niels Henrik; Hvam, Lars; Haug, Anders

    2010-01-01

    This article presents an evaluation of applying a suggested method for modelling product families for product configuration based on theory for modelling mechanical products,systems theory and object-oriented modelling. The modelling technique includes a so-called product variant master and CRC-cards...... the three views. Modelling of characteristics of the product variants in a product family Modelling of constraints between parts in the product family Visualisation of the entire product family on a poster e.g. 1x2 meters The product variant master and CRC-cards are means to bridge the gap between domain...... experts and IT-developers, thus making it possible for the domain experts (e.g. engineers from product development) to express their knowledge in a form that is understandable both for the domain experts and the IT-developers. The product variant master and CRC-cards have currently been tested and further...

  16. Functional significance of rare neuroligin 1 variants found in autism.

    Directory of Open Access Journals (Sweden)

    Moe Nakanishi

    2017-08-01

    Full Text Available Genetic mutations contribute to the etiology of autism spectrum disorder (ASD, a common, heterogeneous neurodevelopmental disorder characterized by impairments in social interaction, communication, and repetitive and restricted patterns of behavior. Since neuroligin3 (NLGN3, a cell adhesion molecule at the neuronal synapse, was first identified as a risk gene for ASD, several additional variants in NLGN3 and NLGN4 were found in ASD patients. Moreover, synaptopathies are now known to cause several neuropsychiatric disorders including ASD. In humans, NLGNs consist of five family members, and neuroligin1 (NLGN1 is a major component forming a complex on excitatory glutamatergic synapses. However, the significance of NLGN1 in neuropsychiatric disorders remains unknown. Here, we systematically examine five missense variants of NLGN1 that were detected in ASD patients, and show molecular and cellular alterations caused by these variants. We show that a novel NLGN1 Pro89Leu (P89L missense variant found in two ASD siblings leads to changes in cellular localization, protein degradation, and to the impairment of spine formation. Furthermore, we generated the knock-in P89L mice, and we show that the P89L heterozygote mice display abnormal social behavior, a core feature of ASD. These results, for the first time, implicate rare variants in NLGN1 as functionally significant and support that the NLGN synaptic pathway is of importance in the etiology of neuropsychiatric disorders.

  17. Cough-variant asthma: a diagnostic dilemma in the occupational setting.

    Science.gov (United States)

    Lipińska-Ojrzanowska, A; Wiszniewska, M; Walusiak-Skorupa, J

    2015-03-01

    Cough-variant asthma (Corrao's syndrome) is defined as the presence of chronic non-productive cough in patients with bronchial hyperresponsiveness (BHR) and response to bronchodilator therapy. This variant of asthma may present a diagnostic problem in occupational medicine. To describe additional evaluation of cough-variant asthma in a cyanoacrylate-exposed worker in whom standard diagnostic testing was negative. A female beautician was evaluated for suspected occupational allergic rhinitis and asthma. A specific inhalation challenge test (SICT) was performed with cyanoacrylate glues used for applying artificial eyelashes and nails. Spirometry and peak expiratory flow (PEF) measurements were recorded hourly for 24h; methacholine challenge testing was performed and nasal lavage (NL) samples were analysed for eosinophilia. After SICT, the patient developed sneezing, nasal airflow obstruction and cough. Declines in forced expiratory volume in 1 s and PEF were not observed. Eosinophil proportions in NL fluid increased markedly at 4 and 24h after SICT. A significant increase in BHR also occurred 24h after SICT. Clinical symptoms, post-challenge BHR and increased NL eosinophil counts confirmed a positive response to SICT and validated the diagnosis of cough-variant occupational asthma. SICT may be useful in cases where history and clinical data suggest cough-variant asthma and spirometric indices are negative. © The Author 2014. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Self-perception in a clinical sample of gender variant children.

    Science.gov (United States)

    Rijn, Anouk Balleur-van; Steensma, Thomas D; Kreukels, Baudewijntje P C; Cohen-Kettenis, Peggy T

    2013-07-01

    Gender variance (GV) in childhood has a negative impact on the self-concept of children in the general population and can lead to mental health problems and even suicidal ideation in adulthood. This study explored the self-concept of clinically referred gender variant children and examined potential risk factors. The Self-Perception Profile for Children was administered to 147 children, who were referred to a gender identity clinic. Their parents completed the Child Behaviour Checklist and the Gender Identity Questionnaire to assess the degree of GV. The referred children were at risk of developing a negative self-concept; more specifically gender variant girls had low scores on 'global self-worth', 'physical appearance' and 'behavioural conduct' compared to Dutch norms for girls. Gender variant boys had low scores on 'global self-worth', 'scholastic competence', 'athletic competence' and 'physical appearance' compared to Dutch norms for boys. Within the group of referred children, sex differences, but no age effects, were found. The referred girls felt more competent than the referred boys on 'athletic competence' and 'scholastic functioning'. For both boys and girls poor peer relations had a significant negative relationship with self-concept and more GV was related to a lower global self-worth. Clinically referred gender variant children seemed vulnerable to developing a negative self-concept. Poor peer relations and extreme GV might be mediating variables. Interventions might focus on enhancing acceptance of the environment and improving social skills of gender variant children.

  19. Distinctive expression pattern of OCT4 variants in different types of breast cancer.

    Science.gov (United States)

    Soheili, Saamaaneh; Asadi, Malek Hossein; Farsinejad, Alireza

    2017-01-01

    OCT4 is a key regulator of self-renewal and pluripotency in embryonic stem cells which can potentially encode three spliced variants designated OCT4A, OCT4B and OCT4B1. Based on cancer stem cell concept, it is suggested that the stemness factors misexpressed in cancer cells and potentially is involved in tumorigenesis. Accordingly, in this study, we investigated the potential expression of OCT4 variants in breast cancer tissues. A total of 94 tumoral and peritumoral breast specimens were evaluated with respect to the expression of OCT4 variants using quantitative RT-PCR and immunohistochemical (IHC) analysis. We detected the expression of OCT4 variants in breast tumor tissues with no or very low levels of expression in peritumoral samples of the same patients. While OCT4B was highly expressed in lobular type of breast cancer, OCT4A and OCTB1 variants are highly expressed in low grade (I and II) ductal tumors. Furthermore, the results of this study revealed a considerable association between the expression level of OCT4 variants and the expression of ER, PR, Her2 and P53 factors. All data demonstrated a distinctive expression pattern of OCT4 spliced variants in different types of breast cancer and provide further evidence for the involvement of embryonic genes in carcinogenesis.

  20. Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar.

    Science.gov (United States)

    Harrison, Steven M; Dolinsky, Jill S; Knight Johnson, Amy E; Pesaran, Tina; Azzariti, Danielle R; Bale, Sherri; Chao, Elizabeth C; Das, Soma; Vincent, Lisa; Rehm, Heidi L

    2017-10-01

    Data sharing through ClinVar offers a unique opportunity to identify interpretation differences between laboratories. As part of a ClinGen initiative, four clinical laboratories (Ambry, GeneDx, Partners Healthcare Laboratory for Molecular Medicine, and University of Chicago Genetic Services Laboratory) collaborated to identify the basis of interpretation differences and to investigate if data sharing and reassessment resolve interpretation differences by analyzing a subset of variants. ClinVar variants with submissions from at least two of the four participating laboratories were compared. For a subset of identified differences, laboratories documented the basis for discordance, shared internal data, independently reassessed with the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines, and then compared interpretations. At least two of the participating laboratories interpreted 6,169 variants in ClinVar, of which 88.3% were initially concordant. Laboratories reassessed 242/724 initially discordant variants, of which 87.2% (211) were resolved by reassessment with current criteria and/or internal data sharing; 12.8% (31) of reassessed variants remained discordant owing to differences in the application of the ACMG-AMP guidelines. Participating laboratories increased their overall concordance from 88.3 to 91.7%, indicating that sharing variant interpretations in ClinVar-thereby allowing identification of differences and motivation to resolve those differences-is critical to moving toward more consistent variant interpretations.Genet Med advance online publication 09 March 2017.

  1. Comparison of statistical tests for association between rare variants and binary traits.

    OpenAIRE

    Bacanu, SA; Nelson, MR; Whittaker, JC

    2012-01-01

    : Genome-wide association studies have found thousands of common genetic variants associated with a wide variety of diseases and other complex traits. However, a large portion of the predicted genetic contribution to many traits remains unknown. One plausible explanation is that some of the missing variation is due to the effects of rare variants. Nonetheless, the statistical analysis of rare variants is challenging. A commonly used method is to contrast, within the same region (gene), the fr...

  2. Evaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines.

    Science.gov (United States)

    Ghosh, Rajarshi; Oak, Ninad; Plon, Sharon E

    2017-11-28

    The American College of Medical Genetics and American College of Pathologists (ACMG/AMP) variant classification guidelines for clinical reporting are widely used in diagnostic laboratories for variant interpretation. The ACMG/AMP guidelines recommend complete concordance of predictions among all in silico algorithms used without specifying the number or types of algorithms. The subjective nature of this recommendation contributes to discordance of variant classification among clinical laboratories and prevents definitive classification of variants. Using 14,819 benign or pathogenic missense variants from the ClinVar database, we compared performance of 25 algorithms across datasets differing in distinct biological and technical variables. There was wide variability in concordance among different combinations of algorithms with particularly low concordance for benign variants. We also identify a previously unreported source of error in variant interpretation (false concordance) where concordant in silico predictions are opposite to the evidence provided by other sources. We identified recently developed algorithms with high predictive power and robust to variables such as disease mechanism, gene constraint, and mode of inheritance, although poorer performing algorithms are more frequently used based on review of the clinical genetics literature (2011-2017). Our analyses identify algorithms with high performance characteristics independent of underlying disease mechanisms. We describe combinations of algorithms with increased concordance that should improve in silico algorithm usage during assessment of clinically relevant variants using the ACMG/AMP guidelines.

  3. m6ASNP: a tool for annotating genetic variants by m6A function.

    Science.gov (United States)

    Jiang, Shuai; Xie, Yubin; He, Zhihao; Zhang, Ya; Zhao, Yuli; Chen, Li; Zheng, Yueyuan; Miao, Yanyan; Zuo, Zhixiang; Ren, Jian

    2018-04-02

    Large-scale genome sequencing projects have identified many genetic variants for diverse diseases. A major goal of these projects is to characterize these genetic variants to provide insight into their function and roles in diseases. N6-methyladenosine (m6A) is one of the most abundant RNA modifications in eukaryotes. Recent studies have revealed that aberrant m6A modifications are involved in many diseases. In this study, we present a user-friendly web server called "m6ASNP" that is dedicated to the identification of genetic variants targeting m6A modification sites. A random forest model was implemented in m6ASNP to predict whether the methylation status of a m6A site is altered by the variants surrounding the site. In m6ASNP, genetic variants in a standard VCF format are accepted as the input data, and the output includes an interactive table containing the genetic variants annotated by m6A function. In addition, statistical diagrams and a genome browser are provided to visualize the characteristics and annotate the genetic variants. We believe that m6ASNP is a highly convenient tool that can be used to boost further functional studies investigating genetic variants. The web server "m6ASNP" is implemented in JAVA and PHP and is freely available at http://m6asnp.renlab.org.

  4. Whole-exome sequencing identifies common and rare variant metabolic QTLs in a Middle Eastern population.

    Science.gov (United States)

    Yousri, Noha A; Fakhro, Khalid A; Robay, Amal; Rodriguez-Flores, Juan L; Mohney, Robert P; Zeriri, Hassina; Odeh, Tala; Kader, Sara Abdul; Aldous, Eman K; Thareja, Gaurav; Kumar, Manish; Al-Shakaki, Alya; Chidiac, Omar M; Mohamoud, Yasmin A; Mezey, Jason G; Malek, Joel A; Crystal, Ronald G; Suhre, Karsten

    2018-01-23

    Metabolomics-genome-wide association studies (mGWAS) have uncovered many metabolic quantitative trait loci (mQTLs) influencing human metabolic individuality, though predominantly in European cohorts. By combining whole-exome sequencing with a high-resolution metabolomics profiling for a highly consanguineous Middle Eastern population, we discover 21 common variant and 12 functional rare variant mQTLs, of which 45% are novel altogether. We fine-map 10 common variant mQTLs to new metabolite ratio associations, and 11 common variant mQTLs to putative protein-altering variants. This is the first work to report common and rare variant mQTLs linked to diseases and/or pharmacological targets in a consanguineous Arab cohort, with wide implications for precision medicine in the Middle East.

  5. Structural comparisons of two allelic variants of human placental alkaline phosphatase.

    Science.gov (United States)

    Millán, J L; Stigbrand, T; Jörnvall, H

    1985-01-01

    A simple immunosorbent purification scheme based on monoclonal antibodies has been devised for human placental alkaline phosphatase. The two most common allelic variants, S and F, have similar amino acid compositions with identical N-terminal amino acid sequences through the first 13 residues. Both variants have identical lectin binding properties towards concanavalin A, lentil-lectin, wheat germ agglutinin, phytohemagglutinin and soybean agglutinin, and identical carbohydrate contents as revealed by methylation analysis. CNBr fragments of the variants demonstrate identical high performance liquid chromatography patterns. The carbohydrate containing fragment is different from the 32P-labeled active site fragment and the N-terminal fragment.

  6. Pan-cancer analysis reveals technical artifacts in TCGA germline variant calls.

    Science.gov (United States)

    Buckley, Alexandra R; Standish, Kristopher A; Bhutani, Kunal; Ideker, Trey; Lasken, Roger S; Carter, Hannah; Harismendy, Olivier; Schork, Nicholas J

    2017-06-12

    Cancer research to date has largely focused on somatically acquired genetic aberrations. In contrast, the degree to which germline, or inherited, variation contributes to tumorigenesis remains unclear, possibly due to a lack of accessible germline variant data. Here we called germline variants on 9618 cases from The Cancer Genome Atlas (TCGA) database representing 31 cancer types. We identified batch effects affecting loss of function (LOF) variant calls that can be traced back to differences in the way the sequence data were generated both within and across cancer types. Overall, LOF indel calls were more sensitive to technical artifacts than LOF Single Nucleotide Variant (SNV) calls. In particular, whole genome amplification of DNA prior to sequencing led to an artificially increased burden of LOF indel calls, which confounded association analyses relating germline variants to tumor type despite stringent indel filtering strategies. The samples affected by these technical artifacts include all acute myeloid leukemia and practically all ovarian cancer samples. We demonstrate how technical artifacts induced by whole genome amplification of DNA can lead to false positive germline-tumor type associations and suggest TCGA whole genome amplified samples be used with caution. This study draws attention to the need to be sensitive to problems associated with a lack of uniformity in data generation in TCGA data.

  7. Exome-Wide Association Study Identifies New Low-Frequency and Rare UGT1A1 Coding Variants and UGT1A6 Coding Variants Influencing Serum Bilirubin in Elderly Subjects

    Science.gov (United States)

    Oussalah, Abderrahim; Bosco, Paolo; Anello, Guido; Spada, Rosario; Guéant-Rodriguez, Rosa-Maria; Chery, Céline; Rouyer, Pierre; Josse, Thomas; Romano, Antonino; Elia, Maurizzio; Bronowicki, Jean-Pierre; Guéant, Jean-Louis

    2015-01-01

    Abstract Genome-wide association studies (GWASs) have identified loci contributing to total serum bilirubin level. However, no exome-wide approaches have been performed to address this question. Using exome-wide approach, we assessed the influence of protein-coding variants on unconjugated, conjugated, and total serum bilirubin levels in a well-characterized cohort of 773 ambulatory elderly subjects from Italy. Coding variants were replicated in 227 elderly subjects from the same area. We identified 4 missense rare (minor allele frequency, MAF bilirubin level (P = 2.34 × 10−34, P = 7.02 × 10−34, and P = 8.27 × 10−34), as well as unconjugated, and conjugated bilirubin levels. We also identified UGT1A6 variants in association with total (rs6759892, p.Ser7Ala, P = 1.98 × 10−26; rs2070959, p.Thr181Ala, P = 2.87 × 10−27; and rs1105879, p.Arg184Ser, P = 3.27 × 10−29), unconjugated, and conjugated bilirubin levels. All UGT1A1 intronic variants (rs887829, rs6742078, and rs4148325) and UGT1A6 coding variants (rs6759892, rs2070959, and rs1105879) were significantly associated with gallstone-related cholecystectomy risk. The UGT1A6 variant rs2070959 (p.Thr181Ala) was associated with the highest risk of gallstone–related cholecystectomy (OR, 4.58; 95% CI, 1.58–13.28; P = 3.21 × 10−3). Using an exome-wide approach we identified coding variants on UGT1A1 and UGT1A6 genes in association with serum bilirubin level and hyperbilirubinemia risk in elderly subjects. UGT1A1 intronic single-nucleotide polymorphisms (SNPs) (rs6742078, rs887829, rs4148324) serve as proxy markers for the low-frequency and rare UGT1A1 variants, thereby providing mechanistic explanation to the relationship between UGT1A1 intronic SNPs and the UGT1A1 enzyme activity. UGT1A1 and UGT1A6 variants might be potentially associated with gallstone-related cholecystectomy risk. PMID:26039129

  8. A Burkholderia pseudomallei colony variant necessary for gastric colonization.

    Science.gov (United States)

    Austin, C R; Goodyear, A W; Bartek, I L; Stewart, A; Sutherland, M D; Silva, E B; Zweifel, A; Vitko, N P; Tuanyok, A; Highnam, G; Mittelman, D; Keim, P; Schweizer, H P; Vázquez-Torres, A; Dow, S W C; Voskuil, M I

    2015-02-03

    Diverse colony morphologies are a hallmark of Burkholderia pseudomallei recovered from infected patients. We observed that stresses that inhibit aerobic respiration shifted populations of B. pseudomallei from the canonical white colony morphotype toward two distinct, reversible, yet relatively stable yellow colony variants (YA and YB). As accumulating evidence supports the importance of B. pseudomallei enteric infection and gastric colonization, we tested the response of yellow variants to hypoxia, acidity, and stomach colonization. Yellow variants exhibited a competitive advantage under hypoxic and acidic conditions and alkalized culture media. The YB variant, although highly attenuated in acute virulence, was the only form capable of colonization and persistence in the murine stomach. The accumulation of extracellular DNA (eDNA) was a characteristic of YB as observed by 4',6-diamidino-2-phenylindole (DAPI) staining of gastric tissues, as well as in an in vitro stomach model where large amounts of eDNA were produced without cell lysis. Transposon mutagenesis identified a transcriptional regulator (BPSL1887, designated YelR) that when overexpressed produced the yellow phenotype. Deletion of yelR blocked a shift from white to the yellow forms. These data demonstrate that YB is a unique B. pseudomallei pathovariant controlled by YelR that is specifically adapted to the harsh gastric environment and necessary for persistent stomach colonization. Seemingly uniform populations of bacteria often contain subpopulations that are genetically identical but display unique characteristics which offer advantages when the population is faced with infrequent but predictable stresses. The pathogen Burkholderia pseudomallei is capable of forming several reversible colony types, and it interconverted between one white type and two yellow types under certain environmental stresses. The two yellow forms exhibited distinct advantages in low-oxygen and acidic environments. One yellow

  9. Variantes de lesões intra-epiteliais escamosas: relato de quatro casos Variants of intraepithelial squamous lesions: report of four cases

    Directory of Open Access Journals (Sweden)

    Álvaro P. Pinto

    2005-04-01

    Full Text Available Entre a rotina de biópsias e produtos cirúrgicos provenientes do colo uterino, um número significativo de lesões intra-epiteliais escamosas (LIE pode causar dificuldade quanto a caracterização e graduação histológica. Tais lesões têm sido identificadas e descritas isoladamente por artigos científicos como variantes histológicas de LIE cervicais. São elas a metaplasia papilar imatura atípica (MPIA e as variantes de neoplasia intra-epitelial cervical graus II/III: queratinizante, com padrão metaplásico imaturo de crescimento e escamomucinosa. Neste artigo são exemplificados quatro casos representativos das entidades citadas acima, provenientes das rotinas do Programa de Prevenção do Câncer Ginecológico do Estado do Paraná e de um laboratório privado especializado em patologia ginecológica de Curitiba, o Laboratório de Citopatologia e Anatomia Patológica Annalab. Os principais critérios diagnósticos são descritos, assim como a correlação citológica e molecular relacionada à presença e à localização do ácido nucleico viral (papilomavírus humano [HPV] nas lesões.In routine basis, among biopsies and surgical specimens derived from uterine cervix, a significant number of squamous intraepithelial lesions (SIL may be difficult to diagnose and grade. Some of these lesions were identified, isolated and reported in scientific articles as histological variants of SIL. They are: metaplastic papillary immature atypia (MPIA and the following grade II/III cervical intraepithelial neoplasia variants: keratinized, immature metaplastic-like proliferation and mucin-producing. In this article four cases representative of these variants are described. They were retrieved from the routines of a large scale gynecological cancer screening program and a private laboratory specialized on gynecological pathology, both from Paraná State, Brazil. The main histological criteria for diagnosis are described, as well cytological and

  10. Joint associations between genetic variants and reproductive factors in glioma risk among women.

    Science.gov (United States)

    Wang, Sophia S; Hartge, Patricia; Yeager, Meredith; Carreón, Tania; Ruder, Avima M; Linet, Martha; Inskip, Peter D; Black, Amanda; Hsing, Ann W; Alavanja, Michael; Beane-Freeman, Laura; Safaiean, Mahboobeh; Chanock, Stephen J; Rajaraman, Preetha

    2011-10-15

    In a pooled analysis of 4 US epidemiologic studies (1993-2001), the authors evaluated the role of 5 female reproductive factors in 357 women with glioma and 822 controls. The authors further evaluated the independent association between 5 implicated gene variants and glioma risk among the study population, as well as the joint associations of female reproductive factors (ages at menarche and menopause, menopausal status, use of oral contraceptives, and menopausal hormone therapy) and these gene variants on glioma risk. Risk estimates were calculated as odds ratios and 95% confidence intervals that were adjusted for age, race, and study. Three of the gene variants (rs4295627, a variant of CCDC26; rs4977756, a variant of CDKN2A and CDKN2B; and rs6010620, a variant of RTEL1) were statistically significantly associated with glioma risk in the present population. Compared with women who had an early age at menarche (<12 years of age), those who reported menarche at 12-13 years of age or at 14 years of age or older had a 1.7-fold higher risk and a 1.9-fold higher risk of glioma, respectively (P for trend = 0.009). Postmenopausal women and women who reported ever having used oral contraceptives had a decreased risk of glioma. The authors did not observe joint associations between these reproductive characteristics and the implicated glioma gene variants. These results require replication, but if confirmed, they would suggest that the gene variants that have previously been implicated in the development of glioma are unlikely to act through the same hormonal mechanisms in women.

  11. Complex Landscape of Germline Variants in Brazilian Patients With Hereditary and Early Onset Breast Cancer

    Directory of Open Access Journals (Sweden)

    Giovana T. Torrezan

    2018-05-01

    Full Text Available Pathogenic variants in known breast cancer (BC predisposing genes explain only about 30% of Hereditary Breast Cancer (HBC cases, whereas the underlying genetic factors for most families remain unknown. Here, we used whole-exome sequencing (WES to identify genetic variants associated to HBC in 17 patients of Brazil with familial BC and negative for causal variants in major BC risk genes (BRCA1/2, TP53, and CHEK2 c.1100delC. First, we searched for rare variants in 27 known HBC genes and identified two patients harboring truncating pathogenic variants in ATM and BARD1. For the remaining 15 negative patients, we found a substantial vast number of rare genetic variants. Thus, for selecting the most promising variants we used functional-based variant prioritization, followed by NGS validation, analysis in a control group, cosegregation analysis in one family and comparison with previous WES studies, shrinking our list to 23 novel BC candidate genes, which were evaluated in an independent cohort of 42 high-risk BC patients. Rare and possibly damaging variants were identified in 12 candidate genes in this cohort, including variants in DNA repair genes (ERCC1 and SXL4 and other cancer-related genes (NOTCH2, ERBB2, MST1R, and RAF1. Overall, this is the first WES study applied for identifying novel genes associated to HBC in Brazilian patients, in which we provide a set of putative BC predisposing genes. We also underpin the value of using WES for assessing the complex landscape of HBC susceptibility, especially in less characterized populations.

  12. Functional Analysis of Cancer-Associated DNA Polymerase ε Variants in Saccharomyces cerevisiae

    Directory of Open Access Journals (Sweden)

    Stephanie R. Barbari

    2018-03-01

    Full Text Available DNA replication fidelity relies on base selectivity of the replicative DNA polymerases, exonucleolytic proofreading, and postreplicative DNA mismatch repair (MMR. Ultramutated human cancers without MMR defects carry alterations in the exonuclease domain of DNA polymerase ε (Polε. They have been hypothesized to result from defective proofreading. However, modeling of the most common variant, Polε-P286R, in yeast produced an unexpectedly strong mutator effect that exceeded the effect of proofreading deficiency by two orders of magnitude and indicated the involvement of other infidelity factors. The in vivo consequences of many additional Polε mutations reported in cancers remain poorly understood. Here, we genetically characterized 13 cancer-associated Polε variants in the yeast system. Only variants directly altering the DNA binding cleft in the exonuclease domain elevated the mutation rate. Among these, frequently recurring variants were stronger mutators than rare variants, in agreement with the idea that mutator phenotype has a causative role in tumorigenesis. In nearly all cases, the mutator effects exceeded those of an exonuclease-null allele, suggesting that mechanisms distinct from loss of proofreading may drive the genome instability in most ultramutated tumors. All mutator alleles were semidominant, supporting the view that heterozygosity for the polymerase mutations is sufficient for tumor development. In contrast to the DNA binding cleft alterations, peripherally located variants, including a highly recurrent V411L, did not significantly elevate mutagenesis. Finally, the analysis of Polε variants found in MMR-deficient tumors suggested that the majority cause no mutator phenotype alone but some can synergize with MMR deficiency to increase the mutation rate.

  13. Time-variant reliability assessment through equivalent stochastic process transformation

    International Nuclear Information System (INIS)

    Wang, Zequn; Chen, Wei

    2016-01-01

    Time-variant reliability measures the probability that an engineering system successfully performs intended functions over a certain period of time under various sources of uncertainty. In practice, it is computationally prohibitive to propagate uncertainty in time-variant reliability assessment based on expensive or complex numerical models. This paper presents an equivalent stochastic process transformation approach for cost-effective prediction of reliability deterioration over the life cycle of an engineering system. To reduce the high dimensionality, a time-independent reliability model is developed by translating random processes and time parameters into random parameters in order to equivalently cover all potential failures that may occur during the time interval of interest. With the time-independent reliability model, an instantaneous failure surface is attained by using a Kriging-based surrogate model to identify all potential failure events. To enhance the efficacy of failure surface identification, a maximum confidence enhancement method is utilized to update the Kriging model sequentially. Then, the time-variant reliability is approximated using Monte Carlo simulations of the Kriging model where system failures over a time interval are predicted by the instantaneous failure surface. The results of two case studies demonstrate that the proposed approach is able to accurately predict the time evolution of system reliability while requiring much less computational efforts compared with the existing analytical approach. - Highlights: • Developed a new approach for time-variant reliability analysis. • Proposed a novel stochastic process transformation procedure to reduce the dimensionality. • Employed Kriging models with confidence-based adaptive sampling scheme to enhance computational efficiency. • The approach is effective for handling random process in time-variant reliability analysis. • Two case studies are used to demonstrate the efficacy

  14. mirVAFC: A Web Server for Prioritizations of Pathogenic Sequence Variants from Exome Sequencing Data via Classifications.

    Science.gov (United States)

    Li, Zhongshan; Liu, Zhenwei; Jiang, Yi; Chen, Denghui; Ran, Xia; Sun, Zhong Sheng; Wu, Jinyu

    2017-01-01

    Exome sequencing has been widely used to identify the genetic variants underlying human genetic disorders for clinical diagnoses, but the identification of pathogenic sequence variants among the huge amounts of benign ones is complicated and challenging. Here, we describe a new Web server named mirVAFC for pathogenic sequence variants prioritizations from clinical exome sequencing (CES) variant data of single individual or family. The mirVAFC is able to comprehensively annotate sequence variants, filter out most irrelevant variants using custom criteria, classify variants into different categories as for estimated pathogenicity, and lastly provide pathogenic variants prioritizations based on classifications and mutation effects. Case studies using different types of datasets for different diseases from publication and our in-house data have revealed that mirVAFC can efficiently identify the right pathogenic candidates as in original work in each case. Overall, the Web server mirVAFC is specifically developed for pathogenic sequence variant identifications from family-based CES variants using classification-based prioritizations. The mirVAFC Web server is freely accessible at https://www.wzgenomics.cn/mirVAFC/. © 2016 WILEY PERIODICALS, INC.

  15. Myopathy With SQSTM1 and TIA1 Variants: Clinical and Pathological Features

    Directory of Open Access Journals (Sweden)

    Zhiyv Niu

    2018-03-01

    Full Text Available ObjectiveThe aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies.Patients and methodsClinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy.ResultsGenetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in SQSTM1 (c.1175C>T, p.Pro392Leu and a heterozygous variant in TIA1 (c.1070A>G, p.Asn357Ser. The affected fraternal twin of one proband also carries both variants, while the unaffected family members harbor one or none. Two unrelated probands (family 1, II.3, and family 3, II.1 have a distal myopathy with rimmed vacuoles that manifested with index extensor weakness; the other proband (family 2, I.1 has myofibrillar myopathy manifesting with hypercapnic respiratory insufficiency and distal weakness.ConclusionThe findings indicate that all the affected individuals have a myopathy associated with both variants in SQSTM1 and TIA1, respectively, suggesting that the two variants determine the phenotype and likely functionally interact. We speculate that the TIA1 variant is a modifier of the SQSTM1 mutation. We identify the combination of SQSTM1 and TIA1 variants as a novel genetic defect associated with myofibrillar myopathy and suggest to consider sequencing both genes in the molecular investigation of myopathy with rimmed vacuoles and myofibrillar myopathy

  16. Myopathy With SQSTM1 and TIA1 Variants: Clinical and Pathological Features.

    Science.gov (United States)

    Niu, Zhiyv; Pontifex, Carly Sabine; Berini, Sarah; Hamilton, Leslie E; Naddaf, Elie; Wieben, Eric; Aleff, Ross A; Martens, Kristina; Gruber, Angela; Engel, Andrew G; Pfeffer, Gerald; Milone, Margherita

    2018-01-01

    The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies. Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy. Genetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in SQSTM1 (c.1175C>T, p.Pro392Leu) and a heterozygous variant in TIA1 (c.1070A>G, p.Asn357Ser). The affected fraternal twin of one proband also carries both variants, while the unaffected family members harbor one or none. Two unrelated probands (family 1, II.3, and family 3, II.1) have a distal myopathy with rimmed vacuoles that manifested with index extensor weakness; the other proband (family 2, I.1) has myofibrillar myopathy manifesting with hypercapnic respiratory insufficiency and distal weakness. The findings indicate that all the affected individuals have a myopathy associated with both variants in SQSTM1 and TIA1 , respectively, suggesting that the two variants determine the phenotype and likely functionally interact. We speculate that the TIA1 variant is a modifier of the SQSTM1 mutation. We identify the combination of SQSTM1 and TIA1 variants as a novel genetic defect associated with myofibrillar myopathy and suggest to consider sequencing both genes in the molecular investigation of myopathy with rimmed vacuoles and myofibrillar myopathy although additional studies are needed to investigate the

  17. MAI-free performance of PMU-OFDM transceiver in time-variant environment

    Science.gov (United States)

    Tadjpour, Layla; Tsai, Shang-Ho; Kuo, C.-C. J.

    2005-06-01

    An approximately multi-user OFDM transceiver was introduced to reduce the multi-access interference (MAI ) due to the carrier frequency offset (CFO) to a negligible amount via precoding by Tsai, Lin and Kuo. In this work, we investigate the performance of this precoded multi-user (PMU) OFDM system in a time-variant channel environment. We analyze and compare the MAI effect caused by time-variant channels in the PMU-OFDM and the OFDMA systems. Generally speaking, the MAI effect consists of two parts. The first part is due to the loss of orthogonality among subchannels for all users while the second part is due to the CFO effect caused by the Doppler shift. Simulation results show that, although OFDMA outperforms the PMU-OFDM transceiver in a fast time-variant environment without CFO, PMU-OFDM outperforms OFDMA in a slow time-variant channel via the use of M/2 symmetric or anti-symmetric codewords of M Hadamard-Walsh codes.

  18. Genetic variants in hormone-related genes and risk of breast cancer.

    Directory of Open Access Journals (Sweden)

    Tess Clendenen

    Full Text Available Sex hormones play a key role in the development of breast cancer. Certain polymorphic variants (SNPs and repeat polymorphisms in hormone-related genes are associated with sex hormone levels. However, the relationship observed between these genetic variants and breast cancer risk has been inconsistent. We conducted a case-control study nested within two prospective cohorts to assess the relationship between specific genetic variants in hormone-related genes and breast cancer risk. In total, 1164 cases and 2111 individually-matched controls were included in the study. We did not observe an association between potential functional genetic polymorphisms in the estrogen pathway, SHBG rs6259, ESR1 rs2234693, CYP19 rs10046 and rs4775936, and UGT1A1 rs8175347, or the progesterone pathway, PGR rs1042838, with the risk of breast cancer. Our results suggest that these genetic variants do not have a strong effect on breast cancer risk.

  19. Identification of low-frequency variants associated with gout and serum uric acid levels

    DEFF Research Database (Denmark)

    Sulem, Patrick; Gudbjartsson, Daniel F; Walters, G Bragi

    2011-01-01

    ,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 × 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 10(-21)). We confirmed.......48 s.d., P = 4.5 × 10(-16)). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits....

  20. Variant Selection during Alpha Precipitation in Titanium Alloys: A Simulation Study

    Science.gov (United States)

    Shi, Rongpei

    Variant selection of alpha phase during its precipitation from beta matrix plays a key role in determining transformation texture and final mechanical properties of alpha/beta and beta titanium alloys. In this study we develop a three-dimensional quantitative phase field model (PFM) to predict variant selection and microstructure evolution during beta to alpha transformation in polycrystalline Ti-6Al-4V under the influence of different processing variables. The model links its inputs directly to thermodynamic and mobility databases, and incorporates crystallography of BCC to HCP transformation, elastic anisotropy, defects within semi-coherent alpha/beta interfaces and elastic inhomogeneities among different beta grains. In particular, microstructure and transformation texture evolution are treated simultaneously via orientation distribution function (ODF) modeling of alpha/beta two-phase microstructure in beta polycrystalline obtained by PFM. It is found that, for a given undercooling, the development of transformation texture of the alpha phase due to variant selection during precipitation depends on both externally applied stress or strain, initial texture state of parent beta sample and internal stress generated by the precipitation reaction itself. Moreover, the growth of pre-existing widmanstatten alpha precipitates is accompanied by selective nucleation and growth of secondary alpha plates of preferred variants. We further develop a crystallographic model based on the ideal Burgers orientation relationship (BOR) between GBalpha and one of the two adjacent beta grains to investigate how a prior beta grain boundary contributes to variant selection of grain boundary allotriomorph (GBalpha). The model is able to predict all possible special beta grain boundaries where GBalpha is able to maintain BOR with two neighboring grain. In particular, the model has been used to evaluate the validity of all current empirical variant selection rules to obtain more insight of

  1. Prions in the Urine of Patients with Variant Creutzfeldt–Jakob Disease

    Science.gov (United States)

    Moda, Fabio; Gambetti, Pierluigi; Notari, Silvio; Concha-Marambio, Luis; Catania, Marcella; Park, Kyung-Won; Maderna, Emanuela; Suardi, Silvia; Haïk, Stéphane; Brandel, Jean-Philippe; Ironside, James; Knight, Richard; Tagliavini, Fabrizio; Soto, Claudio

    2014-01-01

    BACKGROUND Prions, the infectious agents responsible for transmissible spongiform encephalopathies, consist mainly of the misfolded prion protein (PrPSc). The unique mechanism of transmission and the appearance of a variant form of Creutzfeldt–Jakob disease, which has been linked to consumption of prion-contaminated cattle meat, have raised concerns about public health. Evidence suggests that variant Creutzfeldt–Jakob disease prions circulate in body fluids from people in whom the disease is silently incubating. METHODS To investigate whether PrPSc can be detected in the urine of patients with variant Creutzfeldt–Jakob disease, we used the protein misfolding cyclic amplification (PMCA) technique to amplify minute quantities of PrPSc, enabling highly sensitive detection of the protein. We analyzed urine samples from several patients with various transmissible spongiform encephalopathies (variant and sporadic Creutzfeldt–Jakob disease and genetic forms of prion disease), patients with other degenerative or nondegenerative neurologic disorders, and healthy persons. RESULTS PrPSc was detectable only in the urine of patients with variant Creutzfeldt–Jakob disease and had the typical electrophoretic profile associated with this disease. PrPSc was detected in 13 of 14 urine samples obtained from patients with variant Creutzfeldt–Jakob disease and in none of the 224 urine samples obtained from patients with other neurologic diseases and from healthy controls, resulting in an estimated sensitivity of 92.9% (95% confidence interval [CI], 66.1 to 99.8) and a specificity of 100.0% (95% CI, 98.4 to 100.0). The PrPSc concentration in urine calculated by means of quantitative PMCA was estimated at 1×10−16 g per milliliter, or 3×10−21 mol per milliliter, which extrapolates to approximately 40 to 100 oligomeric particles of PrPSc per milliliter of urine. CONCLUSIONS Urine samples obtained from patients with variant Creutzfeldt–Jakob disease contained minute

  2. Prions in the urine of patients with variant Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Moda, Fabio; Gambetti, Pierluigi; Notari, Silvio; Concha-Marambio, Luis; Catania, Marcella; Park, Kyung-Won; Maderna, Emanuela; Suardi, Silvia; Haïk, Stéphane; Brandel, Jean-Philippe; Ironside, James; Knight, Richard; Tagliavini, Fabrizio; Soto, Claudio

    2014-08-07

    Prions, the infectious agents responsible for transmissible spongiform encephalopathies, consist mainly of the misfolded prion protein (PrP(Sc)). The unique mechanism of transmission and the appearance of a variant form of Creutzfeldt-Jakob disease, which has been linked to consumption of prion-contaminated cattle meat, have raised concerns about public health. Evidence suggests that variant Creutzfeldt-Jakob disease prions circulate in body fluids from people in whom the disease is silently incubating. To investigate whether PrP(Sc) can be detected in the urine of patients with variant Creutzfeldt-Jakob disease, we used the protein misfolding cyclic amplification (PMCA) technique to amplify minute quantities of PrP(Sc), enabling highly sensitive detection of the protein. We analyzed urine samples from several patients with various transmissible spongiform encephalopathies (variant and sporadic Creutzfeldt-Jakob disease and genetic forms of prion disease), patients with other degenerative or nondegenerative neurologic disorders, and healthy persons. PrP(Sc) was detectable only in the urine of patients with variant Creutzfeldt-Jakob disease and had the typical electrophoretic profile associated with this disease. PrP(Sc) was detected in 13 of 14 urine samples obtained from patients with variant Creutzfeldt-Jakob disease and in none of the 224 urine samples obtained from patients with other neurologic diseases and from healthy controls, resulting in an estimated sensitivity of 92.9% (95% confidence interval [CI], 66.1 to 99.8) and a specificity of 100.0% (95% CI, 98.4 to 100.0). The PrP(Sc) concentration in urine calculated by means of quantitative PMCA was estimated at 1×10(-16) g per milliliter, or 3×10(-21) mol per milliliter, which extrapolates to approximately 40 to 100 oligomeric particles of PrP(Sc) per milliliter of urine. Urine samples obtained from patients with variant Creutzfeldt-Jakob disease contained minute quantities of PrP(Sc). (Funded by the

  3. A novel ALS-associated variant in UBQLN4 regulates motor axon morphogenesis

    Science.gov (United States)

    Edens, Brittany M; Yan, Jianhua; Miller, Nimrod; Deng, Han-Xiang; Siddique, Teepu; Ma, Yongchao C

    2017-01-01

    The etiological underpinnings of amyotrophic lateral sclerosis (ALS) are complex and incompletely understood, although contributions to pathogenesis by regulators of proteolytic pathways have become increasingly apparent. Here, we present a novel variant in UBQLN4 that is associated with ALS and show that its expression compromises motor axon morphogenesis in mouse motor neurons and in zebrafish. We further demonstrate that the ALS-associated UBQLN4 variant impairs proteasomal function, and identify the Wnt signaling pathway effector beta-catenin as a UBQLN4 substrate. Inhibition of beta-catenin function rescues the UBQLN4 variant-induced motor axon phenotypes. These findings provide a strong link between the regulation of axonal morphogenesis and a new ALS-associated gene variant mediated by protein degradation pathways. DOI: http://dx.doi.org/10.7554/eLife.25453.001 PMID:28463112

  4. Two new splice variants in porcine PPARGC1A

    Directory of Open Access Journals (Sweden)

    Peelman Luc J

    2008-12-01

    Full Text Available Abstract Background Peroxisome proliferator-activated receptor γ coactivator 1α (PPARGC1A is a coactivator with a vital and central role in fat and energy metabolism. It is considered to be a candidate gene for meat quality in pigs and is involved in the development of obesity and diabetes in humans. How its many functions are regulated, is however still largely unclear. Therefore a transcription profile of PPARGC1A in 32 tissues and 4 embryonic developmental stages in the pig was constructed by screening its cDNA for possible splice variants with exon-spanning primers. Findings This led to the discovery of 2 new splice variants in the pig, which were subsequently also detected in human tissues. In these variants, exon 8 was either completely or partly (the last 66 bp were conserved spliced out, potentially coding for a much shorter protein of respectively 337 and 359 amino acids (aa, of which the first 291 aa would be the same compared to the complete protein (796 aa. Conclusion Considering the functional domains of the PPARGC1A protein, it is very likely these splice variants considerably affect the function of the protein and alternative splicing could be one of the mechanisms by which the diverse functions of PPARGC1A are regulated.

  5. DAR, a new RhD variant involving exons 4, 5, and 7, often in linkage with ceAR, a new Rhce variant frequently found in African blacks

    NARCIS (Netherlands)

    M.B. Hemker (Mirte); P.C. Ligthart; L. Berger (Loïc); D.J. van Rhenen (Dirk Jan); C.E. van der Schoot (Ellen); P.A. Wijk

    1999-01-01

    textabstractThe highly polymorphic Rh system is encoded by 2 homologous genes RHD and RHCE. Gene rearrangements, deletions, or point mutations may cause partial D and CE antigens. In this study, a new RHD variant, DAR, and a new RHCE variant, ceAR, are described in 4

  6. The Saccharomyces Genome Database Variant Viewer.

    Science.gov (United States)

    Sheppard, Travis K; Hitz, Benjamin C; Engel, Stacia R; Song, Giltae; Balakrishnan, Rama; Binkley, Gail; Costanzo, Maria C; Dalusag, Kyla S; Demeter, Janos; Hellerstedt, Sage T; Karra, Kalpana; Nash, Robert S; Paskov, Kelley M; Skrzypek, Marek S; Weng, Shuai; Wong, Edith D; Cherry, J Michael

    2016-01-04

    The Saccharomyces Genome Database (SGD; http://www.yeastgenome.org) is the authoritative community resource for the Saccharomyces cerevisiae reference genome sequence and its annotation. In recent years, we have moved toward increased representation of sequence variation and allelic differences within S. cerevisiae. The publication of numerous additional genomes has motivated the creation of new tools for their annotation and analysis. Here we present the Variant Viewer: a dynamic open-source web application for the visualization of genomic and proteomic differences. Multiple sequence alignments have been constructed across high quality genome sequences from 11 different S. cerevisiae strains and stored in the SGD. The alignments and summaries are encoded in JSON and used to create a two-tiered dynamic view of the budding yeast pan-genome, available at http://www.yeastgenome.org/variant-viewer. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  7. A PYY Q62P variant linked to human obesity

    Energy Technology Data Exchange (ETDEWEB)

    Ahituv, Nadav; Kavaslar, Nihan; Schackwitz, Wendy; Ustaszewska,Anna; Collier, John Michael; Hebert, Sybil; Doelle, Heather; Dent,Robert; Pennacchio, Len A.; McPherson, Ruth

    2005-06-27

    Members of the pancreatic polypeptide family and the irreceptors have been implicated in the control of food intake in rodents and humans. To investigate whether nucleotide changes in these candidate genes result in abnormal weight in humans, we sequenced the coding exons and splice sites of seven family members (NPY, PYY, PPY, NPY1R, NPY2R, NPY4R, and NPY5R) in a large cohort of extremely obese (n=379) and lean (n=378) individuals. In total we found eleven rare non-synonymous variants, four of which exhibited familial segregation, NPY1R L53P and PPY P63L with leanness and NPY2R D42G and PYY Q62P with obesity. Functional analysis of the obese variants revealed NPY2R D42G to have reduced cell surface expression, while previous cell culture based studies indicated variant PYY Q62P to have altered receptor binding selectivity and we show that it fails to reduce food intake through mouse peptide injection experiments. These results support that rare non-synonymous variants within these genes can alter susceptibility to human body mass index extremes.

  8. Identification of Candidate Gene Variants in Korean MODY Families by Whole-Exome Sequencing.

    Science.gov (United States)

    Shim, Ye Jee; Kim, Jung Eun; Hwang, Su-Kyeong; Choi, Bong Seok; Choi, Byung Ho; Cho, Eun-Mi; Jang, Kyoung Mi; Ko, Cheol Woo

    2015-01-01

    To date, 13 genes causing maturity-onset diabetes of the young (MODY) have been identified. However, there is a big discrepancy in the genetic locus between Asian and Caucasian patients with MODY. Thus, we conducted whole-exome sequencing in Korean MODY families to identify causative gene variants. Six MODY probands and their family members were included. Variants in the dbSNP135 and TIARA databases for Koreans and the variants with minor allele frequencies >0.5% of the 1000 Genomes database were excluded. We selected only the functional variants (gain of stop codon, frameshifts and nonsynonymous single-nucleotide variants) and conducted a case-control comparison in the family members. The selected variants were scanned for the previously introduced gene set implicated in glucose metabolism. Three variants c.620C>T:p.Thr207Ile in PTPRD, c.559C>G:p.Gln187Glu in SYT9, and c.1526T>G:p.Val509Gly in WFS1 were respectively identified in 3 families. We could not find any disease-causative alleles of known MODY 1-13 genes. Based on the predictive program, Thr207Ile in PTPRD was considered pathogenic. Whole-exome sequencing is a valuable method for the genetic diagnosis of MODY. Further evaluation is necessary about the role of PTPRD, SYT9 and WFS1 in normal insulin release from pancreatic beta cells. © 2015 S. Karger AG, Basel.

  9. Postnatal Expression of V2 Vasopressin Receptor Splice Variants in the Rat Cerebellum

    Science.gov (United States)

    Vargas, Karina J.; Sarmiento, José M.; Ehrenfeld, Pamela; Añazco, Carolina C.; Villanueva, Carolina I.; Carmona, Pamela L.; Brenet, Marianne; Navarro, Javier; Müller-Esterl, Werner; Figueroa, Carlos D.; González, Carlos B.

    2010-01-01

    The V2 vasopressin receptor gene contains an alternative splice site in exon-3, which leads to the generation of two splice variants (V2a and V2b) first identified in the kidney. The open reading frame of the alternatively spliced V2b transcripten codes a truncated receptor, showing the same amino acid sequence as the canonical V2a receptor up to the 6th transmembrane segment, but displaying a distinct sequence to the corresponding 7th transmembrane segment and C-terminal domain relative to the V2a receptor. Here, we demonstrate the postnatal expression of V2a and V2b variants in the rat cerebellum. Most importantly, we showed by in situ hybridization and immunocytochemistry that both V2 splice variants were preferentially expressed in Purkinje cells, from early to late postnatal development. In addition, both variants were transiently expressed in the neuroblastic external granule cells and Bergmann fibers. These results indicate that the cellular distributions of both splice variants are developmentally regulated, and suggest that the transient expression of the V2 receptor is involved in the mechanisms of cerebellar cytodifferentiation by AVP. Finally, transfected CHO-K1 .expressing similar amounts of both V2 splice variants, as that found in the cerebellum, showed a significant reduction in the surface expression of V2a receptors, suggesting that the differential expression of the V2 splice variants regulate the vasopressin signaling in the cerebellum. PMID:19281786

  10. Evaluation of type 2 diabetes genetic risk variants in Chinese adults

    DEFF Research Database (Denmark)

    Gan, Wei; Walters, Robin G; Holmes, Michael V

    2016-01-01

    : Association signals were directionally consistent between CKB and the original discovery GWAS: of 56 variants passing quality control, 48 showed the same direction of effect (binomial test, p = 2.3 × 10(-8)). We observed a consistent overall trend towards lower risk variant effect sizes in CKB than in case......-control samples of GWAS meta-analyses (mean 19-22% decrease in log odds, p ≤ 0.0048), likely to reflect correction of both 'winner's curse' and spectrum bias effects. The association with risk of diabetes of a genetic risk score, based on lead variants at 25 loci considered to act through beta cell function...

  11. GxGrare: gene-gene interaction analysis method for rare variants from high-throughput sequencing data.

    Science.gov (United States)

    Kwon, Minseok; Leem, Sangseob; Yoon, Joon; Park, Taesung

    2018-03-19

    With the rapid advancement of array-based genotyping techniques, genome-wide association studies (GWAS) have successfully identified common genetic variants associated with common complex diseases. However, it has been shown that only a small proportion of the genetic etiology of complex diseases could be explained by the genetic factors identified from GWAS. This missing heritability could possibly be explained by gene-gene interaction (epistasis) and rare variants. There has been an exponential growth of gene-gene interaction analysis for common variants in terms of methodological developments and practical applications. Also, the recent advancement of high-throughput sequencing technologies makes it possible to conduct rare variant analysis. However, little progress has been made in gene-gene interaction analysis for rare variants. Here, we propose GxGrare which is a new gene-gene interaction method for the rare variants in the framework of the multifactor dimensionality reduction (MDR) analysis. The proposed method consists of three steps; 1) collapsing the rare variants, 2) MDR analysis for the collapsed rare variants, and 3) detect top candidate interaction pairs. GxGrare can be used for the detection of not only gene-gene interactions, but also interactions within a single gene. The proposed method is illustrated with 1080 whole exome sequencing data of the Korean population in order to identify causal gene-gene interaction for rare variants for type 2 diabetes. The proposed GxGrare performs well for gene-gene interaction detection with collapsing of rare variants. GxGrare is available at http://bibs.snu.ac.kr/software/gxgrare which contains simulation data and documentation. Supported operating systems include Linux and OS X.

  12. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis

    NARCIS (Netherlands)

    Rivas, Manuel A.; Graham, Daniel; Sulem, Patrick; Stevens, Christine; Desch, A. Nicole; Goyette, Philippe; Gudbjartsson, Daniel; Jonsdottir, Ingileif; Thorsteinsdottir, Unnur; Degenhardt, Frauke; Mucha, Soeren; Kurki, Mitja I.; Li, Dalin; D'Amato, Mauro; Annese, Vito; Vermeire, Severine; Weersma, Rinse K.; Halfvarson, Jonas; Paavola-Sakki, Paulina; Lappalainen, Maarit; Lek, Monkol; Cummings, Beryl; Tukiainen, Taru; Haritunians, Talin; Halme, Leena; Koskinen, Lotta L. E.; Ananthakrishnan, Ashwin N.; Luo, Yang; Heap, Graham A.; Visschedijk, Marijn C.; MacArthur, Daniel G.; Neale, Benjamin M.; Ahmad, Tariq; Anderson, Carl A.; Brant, Steven R.; Duerr, Richard H.; Silverberg, Mark S.; Cho, Judy H.; Palotie, Aarno; Saavalainen, Paivi; Kontula, Kimmo; Farkkila, Martti; McGovern, Dermot P. B.; Franke, Andre; Stefansson, Kari; Rioux, John D.; Xavier, Ramnik J.; Daly, Mark J.

    Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants

  13. TDP-43 protein variants as biomarkers in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Williams, Stephanie M; Khan, Galam; Harris, Brent T; Ravits, John; Sierks, Michael R

    2017-01-25

    TDP-43 aggregates accumulate in individuals affected by amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases, representing potential diagnostic and therapeutic targets. Using an atomic force microscopy based biopanning protocol developed in our lab, we previously isolated 23 TDP-43 reactive antibody fragments with preference for human ALS brain tissue relative to frontotemporal dementia, a related neurodegeneration, and healthy samples from phage-displayed single chain antibody fragment (scFv) libraries. Here we further characterize the binding specificity of these different scFvs and identify which ones have promise for detecting ALS biomarkers in human brain tissue and plasma samples. We developed a sensitive capture ELISA for detection of different disease related TDP-43 variants using the scFvs identified from the ALS biopanning. We show that a wide variety of disease selective TDP-43 variants are present in ALS as the scFvs show different reactivity profiles amongst the ALS cases. When assaying individual human brain tissue cases, three scFvs (ALS-TDP6, ALS-TDP10 and ALS-TDP14) reacted with all the ALS cases and 12 others reacted with the majority of the ALS cases, and none of the scFvs reacted with any control samples. When assaying individual human plasma samples, 9 different scFvs reacted with all the sporadic ALS samples and again none of them reacted with any control samples. These 9 different scFvs had different patterns of reactivity with plasma samples obtained from chromosome 9 open reading frame 72 (c9orf72) cases indicating that these familial ALS genetic variants may display different TDP-43 pathology than sporadic ALS cases. These results indicated that a range of disease specific TDP-43 variants are generated in ALS patients with different variants being generated in sporadic and familial cases. We show that a small panel of scFvs recognizing different TDP-43 variants can generate a neuropathological and plasma biomarker

  14. Cystinuria Associated with Different SLC7A9 Gene Variants in the Cat.

    Directory of Open Access Journals (Sweden)

    Keijiro Mizukami

    Full Text Available Cystinuria is a classical inborn error of metabolism characterized by a selective proximal renal tubular defect affecting cystine, ornithine, lysine, and arginine (COLA reabsorption, which can lead to uroliths and urinary obstruction. In humans, dogs and mice, cystinuria is caused by variants in one of two genes, SLC3A1 and SLC7A9, which encode the rBAT and bo,+AT subunits of the bo,+ basic amino acid transporter system, respectively. In this study, exons and flanking regions of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA of cats (Felis catus with COLAuria and cystine calculi. Relative to the Felis catus-6.2 reference genome sequence, DNA sequences from these affected cats revealed 3 unique homozygous SLC7A9 missense variants: one in exon 5 (p.Asp236Asn from a non-purpose-bred medium-haired cat, one in exon 7 (p.Val294Glu in a Maine Coon and a Sphinx cat, and one in exon 10 (p.Thr392Met from a non-purpose-bred long-haired cat. A genotyping assay subsequently identified another cystinuric domestic medium-haired cat that was homozygous for the variant originally identified in the purebred cats. These missense variants result in deleterious amino acid substitutions of highly conserved residues in the bo,+AT protein. A limited population survey supported that the variants found were likely causative. The remaining 2 sequenced domestic short-haired cats had a heterozygous variant at a splice donor site in intron 10 and a homozygous single nucleotide variant at a branchpoint in intron 11 of SLC7A9, respectively. This study identifies the first SLC7A9 variants causing feline cystinuria and reveals that, as in humans and dogs, this disease is genetically heterogeneous in cats.

  15. XVCL: XML-based Variant Configuration Language

    DEFF Research Database (Denmark)

    Jarzabek, Stan; Basset, Paul; Zhang, Hongyu

    2003-01-01

    XVCL (XML-based Variant Configuration Language) is a meta-programming technique and tool that provides effective reuse mechanisms. XVCL is an open source software developed at the National University of Singapore. Being a modern and versatile version of Bassett's frames, a technology that has...

  16. Locus Reference Genomic sequences: An improved basis for describing human DNA variants

    KAUST Repository

    Dalgleish, Raymond; Flicek, Paul; Cunningham, Fiona; Astashyn, Alex; Tully, Raymond E; Proctor, Glenn; Chen, Yuan; McLaren, William M; Larsson, Pontus; Vaughan, Brendan W; Bé roud, Christophe; Dobson, Glen; Lehvä slaiho, Heikki; Taschner, Peter EM; den Dunnen, Johan T; Devereau, Andrew; Birney, Ewan; Brookes, Anthony J; Maglott, Donna R

    2010-01-01

    As our knowledge of the complexity of gene architecture grows, and we increase our understanding of the subtleties of gene expression, the process of accurately describing disease-causing gene variants has become increasingly problematic. In part, this is due to current reference DNA sequence formats that do not fully meet present needs. Here we present the Locus Reference Genomic (LRG) sequence format, which has been designed for the specifi c purpose of gene variant reporting. The format builds on the successful National Center for Biotechnology Information (NCBI) RefSeqGene project and provides a single-fi le record containing a uniquely stable reference DNA sequence along with all relevant transcript and protein sequences essential to the description of gene variants. In principle, LRGs can be created for any organism, not just human. In addition, we recognize the need to respect legacy numbering systems for exons and amino acids and the LRG format takes account of these. We hope that widespread adoption of LRGs - which will be created and maintained by the NCBI and the European Bioinformatics Institute (EBI) - along with consistent use of the Human Genome Variation Society (HGVS)- approved variant nomenclature will reduce errors in the reporting of variants in the literature and improve communication about variants aff ecting human health. Further information can be found on the LRG web site (http://www.lrg-sequence.org). 2010 Dalgleish et al.; licensee BioMed Central Ltd.

  17. Locus Reference Genomic sequences: An improved basis for describing human DNA variants

    KAUST Repository

    Dalgleish, Raymond

    2010-04-15

    As our knowledge of the complexity of gene architecture grows, and we increase our understanding of the subtleties of gene expression, the process of accurately describing disease-causing gene variants has become increasingly problematic. In part, this is due to current reference DNA sequence formats that do not fully meet present needs. Here we present the Locus Reference Genomic (LRG) sequence format, which has been designed for the specifi c purpose of gene variant reporting. The format builds on the successful National Center for Biotechnology Information (NCBI) RefSeqGene project and provides a single-fi le record containing a uniquely stable reference DNA sequence along with all relevant transcript and protein sequences essential to the description of gene variants. In principle, LRGs can be created for any organism, not just human. In addition, we recognize the need to respect legacy numbering systems for exons and amino acids and the LRG format takes account of these. We hope that widespread adoption of LRGs - which will be created and maintained by the NCBI and the European Bioinformatics Institute (EBI) - along with consistent use of the Human Genome Variation Society (HGVS)- approved variant nomenclature will reduce errors in the reporting of variants in the literature and improve communication about variants aff ecting human health. Further information can be found on the LRG web site (http://www.lrg-sequence.org). 2010 Dalgleish et al.; licensee BioMed Central Ltd.

  18. A new approach for reliability analysis with time-variant performance characteristics

    International Nuclear Information System (INIS)

    Wang, Zequn; Wang, Pingfeng

    2013-01-01

    Reliability represents safety level in industry practice and may variant due to time-variant operation condition and components deterioration throughout a product life-cycle. Thus, the capability to perform time-variant reliability analysis is of vital importance in practical engineering applications. This paper presents a new approach, referred to as nested extreme response surface (NERS), that can efficiently tackle time dependency issue in time-variant reliability analysis and enable to solve such problem by easily integrating with advanced time-independent tools. The key of the NERS approach is to build a nested response surface of time corresponding to the extreme value of the limit state function by employing Kriging model. To obtain the data for the Kriging model, the efficient global optimization technique is integrated with the NERS to extract the extreme time responses of the limit state function for any given system input. An adaptive response prediction and model maturation mechanism is developed based on mean square error (MSE) to concurrently improve the accuracy and computational efficiency of the proposed approach. With the nested response surface of time, the time-variant reliability analysis can be converted into the time-independent reliability analysis and existing advanced reliability analysis methods can be used. Three case studies are used to demonstrate the efficiency and accuracy of NERS approach

  19. Genetic epidemiology of motor neuron disease-associated variants in the Scottish population.

    Science.gov (United States)

    Black, Holly A; Leighton, Danielle J; Cleary, Elaine M; Rose, Elaine; Stephenson, Laura; Colville, Shuna; Ross, David; Warner, Jon; Porteous, Mary; Gorrie, George H; Swingler, Robert; Goldstein, David; Harms, Matthew B; Connick, Peter; Pal, Suvankar; Aitman, Timothy J; Chandran, Siddharthan

    2017-03-01

    Genetic understanding of motor neuron disease (MND) has evolved greatly in the past 10 years, including the recent identification of association between MND and variants in TBK1 and NEK1. Our aim was to determine the frequency of pathogenic variants in known MND genes and to assess whether variants in TBK1 and NEK1 contribute to the burden of MND in the Scottish population. SOD1, TARDBP, OPTN, TBK1, and NEK1 were sequenced in 441 cases and 400 controls. In addition to 44 cases known to carry a C9orf72 hexanucleotide repeat expansion, we identified 31 cases and 2 controls that carried a loss-of-function or pathogenic variant. Loss-of-function variants were found in TBK1 in 3 cases and no controls and, separately, in NEK1 in 3 cases and no controls. This study provides an accurate description of the genetic epidemiology of MND in Scotland and provides support for the contribution of both TBK1 and NEK1 to MND susceptibility in the Scottish population. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Molecular Background of Colorectal Tumors From Patients with Lynch Syndrome Associated With Germline Variants in PMS2.

    Science.gov (United States)

    Ten Broeke, S W; van Bavel, T C; Jansen, A M L; Gómez-García, E; Hes, F J; van Hest, L P; Letteboer, T G W; Olderode-Berends, M J W; Ruano, D; Spruijt, L; Suerink, M; Tops, C M; van Eijk, R; Morreau, H; van Wezel, T; Nielsen, M

    2018-05-11

    Germline variants in the mismatch repair genes MLH1, MSH2 (EPCAM), MSH6, or PMS2 cause Lynch syndrome. Patients with these variants have an increased risk of developing colorectal cancers (CRCs) that differ from sporadic CRCs in genetic and histologic features. It has been a challenge to study CRCs associated with PMS2 variants (PMS2-associated CRCs) because these develop less frequently and in patients of older ages than colorectal tumors with variants in the other mismatch repair genes. We analyzed 20 CRCs associated with germline variants in PMS2, 22 sporadic CRCs, 18 CRCs with germline variants in MSH2, and 24 CRCs from patients with germline variants in MLH1. Tumor tissue blocks were collected from Dutch pathology departments in 2017. After extraction of tumor DNA, we used a platform designed to detect approximately 3000 somatic hotspot variants in 55 genes (including KRAS, APC, CTNNB1, and TP53). Somatic variant frequencies were compared using the Fisher's exact test. None of the PMS2-associated CRCs contained any somatic variants in the catenin beta 1 gene (CTNNB1), which encodes β-catenin, whereas 14/24 MLH1-associated CRCs (58%) contained variants in CTNNB1. Half of PMS2-associated CRCs contained KRAS variants, but only 20% of these were in hotspots that encoded G12D or G13D. These hotspot variants occurred more frequently in CRCs associated with variants in MLH1 (37.5%, P=.44) and MSH2 (and 71.4%, P=.035) than with variants in PMS2. In a genetic analysis of 84 colorectal tumors, we found tumors from patients with PMS2-associated Lynch syndrome to be distinct from colorectal tumors associated with defects in other mismatch repair genes. This might account for differences in development and less frequent occurrence. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

  1. Integrated genomic and transcriptomic analysis reveals mycoparasitism as the ancestoral life style of Trichoderma

    Energy Technology Data Exchange (ETDEWEB)

    Kubicek, Christian P.; Herrera-Estrella, Alfredo; Seidl, Verena; Crom, St& #233; phane Le; Martinez, Diego A.; Druzhinina, Irina S.; Zeilinger, Susanne; Casas-Flores, Sergio; Horwitz, Benjamin A.; Mukherjee, Prasun K.; Mukherjee, Mala; Kredics, L& #225; szlo; Alcaraz, Luis David; Aerts, Andrea; Antal, Zsuzsanna; Atanasova, Lea; Cervantes-Badillo, Mayte Guadalupe; Challacombe, Jean; Chertkov, Olga; McCluskey, Kevin; Coulpier, Fanny; Deshpande, Nandan; D& #246; hren, Hans von; Ebbole, Daniel J.; Esquivel-Naranjo, Edgardo Ulises; Fekete, Erzs& #233; bet; Flipphi, Michel; Glaser, Fabian; Gomez-Rodriguez, Elida Yazmin; Gruber, Sabine; Han, Cliff; Henrissat, Bernard; Hermosa, Rosa; Hern& #225; ndez-O?ate, Miguel; Karaffa, Levente; Kosti, Idit; Lindquist, Erika; Lucas, Susan; L& #252; beck, Mette; L& #252; beck, Peter Stephensen; Margeot, Antoine; Metz, Benjamin; Misra, Monica; Nevalainen, Helena; Omann, Markus; Packer, Nicolle; Perrone, Giancarlo; Uresti-Rivera, Edith Elena; Salamov, Asaf; Schmoll, Monika; Seiboth, Bernhard; Shapiro, Harris; Sukno, Serenella; Tamayo-Ramos, Juan Antonio; Thon, Michael; Tisch, Doris; Wiest, Aric; Wilkinson, Heather H.; Zhang, Michael; Coutinho, Pedro M.; Kenerley, Charles M.; Monte, Enrique; Baker, Scott E.; Grigoriev, Igor V.

    2011-04-29

    Mycoparasitism, a lifestyle where one fungus is parasitic on another fungus has special relevance when the prey is a plant pathogen, providing a strategy for biological control of pests for plant protection. Probably, the most studied biocontrol agents are species of the genus Hypocrea/Trichoderma.

  2. Amino acid substitutions in inherited albumin variants from Amerindian and Japanese populations

    International Nuclear Information System (INIS)

    Takahashi, N.; Takahashi, Y.; Isobe, T.; Putnam, F.W.; Fujita, M.; Satoh, C.; Neel, J.V.

    1987-01-01

    The authors report an effort to determine the basis for the altered migration of seven inherited albumin variants detected by one-dimensional electrophoresis in population surveys involving tribal Amerindians and Japanese children. An amino acid substitution has thus far been determined for four of the variants. The randomness in the albumin polypeptide of these and the other sixteen independently ascertained amino acid substitutions of albumin and proalbumin thus far established was analyzed; the clustering of eight of these at two positions in the six-amino acid propeptide sequence seems noteworthy. By comparison with other proteins studied by electrophoresis, albumin exhibits average variability. It is a paradox that individuals who, for genetic reasons, lack albumin exhibit no obvious ill effects; yet, electrophoretic variants of albumin are no more numerous than are variants of proteins, the absence of which results in severe disease

  3. Odontogenic keratocyst: a peripheral variant.

    Science.gov (United States)

    Vij, H; Vij, R; Gupta, V; Sengupta, S

    2011-01-01

    Odontogenic keratocyst, which is developmental in nature, is an intraosseous lesion though on rare occasions it may occur in an extraosseous location. The extraosseous variant is referred to as peripheral odontogenic keratocyst. Though, clinically, peripheral odontogenic keratocyst resembles the gingival cyst of adults, it has histologic features that are pathognomonic of odontogenic keratocyst. This article presents a case of this uncommon entity.

  4. Genetic Variants in Transcription Factors Are Associated With the Pharmacokinetics and Pharmacodynamics of Metformin

    Science.gov (United States)

    Goswami, S; Yee, SW; Stocker, S; Mosley, JD; Kubo, M; Castro, R; Mefford, JA; Wen, C; Liang, X; Witte, J; Brett, C; Maeda, S; Simpson, MD; Hedderson, MM; Davis, RL; Roden, DM; Giacomini, KM; Savic, RM

    2014-01-01

    One-third of type 2 diabetes patients do not respond to metformin. Genetic variants in metformin transporters have been extensively studied as a likely contributor to this high failure rate. Here, we investigate, for the first time, the effect of genetic variants in transcription factors on metformin pharmacokinetics (PK) and response. Overall, 546 patients and healthy volunteers contributed their genome-wide, pharmacokinetic (235 subjects), and HbA1c data (440 patients) for this analysis. Five variants in specificity protein 1 (SP1), a transcription factor that modulates the expression of metformin transporters, were associated with changes in treatment HbA1c (P < 0.01) and metformin secretory clearance (P < 0.05). Population pharmacokinetic modeling further confirmed a 24% reduction in apparent clearance in homozygous carriers of one such variant, rs784888. Genetic variants in other transcription factors, peroxisome proliferator–activated receptor-α and hepatocyte nuclear factor 4-α, were significantly associated with HbA1c change only. Overall, our study highlights the importance of genetic variants in transcription factors as modulators of metformin PK and response. PMID:24853734

  5. DAR, a new RhD variant involving exons 4, 5, and 7, often in linkage with ceAR, a new Rhce variant frequently found in African blacks

    NARCIS (Netherlands)

    Hemker, M. B.; Ligthart, P. C.; Berger, L.; van Rhenen, D. J.; van der Schoot, C. E.; Wijk, P. A.

    1999-01-01

    The highly polymorphic Rh system is encoded by 2 homologous genes RHD and RHCE. Gene rearrangements, deletions, or point mutations may cause partial D and CE antigens. In this study, a new RHD variant, DAR, and a new RHCE variant, ceAR, are described in 4 Dutch African Blacks. Serologically, DAR

  6. Functional assays for analysis of variants of uncertain significance in BRCA2

    DEFF Research Database (Denmark)

    Guidugli, Lucia; Carreira, Aura; Caputo, Sandrine M

    2014-01-01

    Missense variants in the BRCA2 gene are routinely detected during clinical screening for pathogenic mutations in patients with a family history of breast and ovarian cancer. These subtle changes frequently remain of unknown clinical significance because of the lack of genetic information that may...... of uncertain significance analyzed, and describe a validation set of (genetically) proven pathogenic and neutral missense variants to serve as a golden standard for the validation of each assay. Guidelines are proposed to enable implementation of laboratory-based methods to assess the impact of the variant...

  7. Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits

    DEFF Research Database (Denmark)

    Chami, Nathalie; Chen, Ming-Huei; Slater, Andrew J

    2016-01-01

    array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p

  8. Engineered Cpf1 variants with altered PAM specificities.

    Science.gov (United States)

    Gao, Linyi; Cox, David B T; Yan, Winston X; Manteiga, John C; Schneider, Martin W; Yamano, Takashi; Nishimasu, Hiroshi; Nureki, Osamu; Crosetto, Nicola; Zhang, Feng

    2017-08-01

    The RNA-guided endonuclease Cpf1 is a promising tool for genome editing in eukaryotic cells. However, the utility of the commonly used Acidaminococcus sp. BV3L6 Cpf1 (AsCpf1) and Lachnospiraceae bacterium ND2006 Cpf1 (LbCpf1) is limited by their requirement of a TTTV protospacer adjacent motif (PAM) in the DNA substrate. To address this limitation, we performed a structure-guided mutagenesis screen to increase the targeting range of Cpf1. We engineered two AsCpf1 variants carrying the mutations S542R/K607R and S542R/K548V/N552R, which recognize TYCV and TATV PAMs, respectively, with enhanced activities in vitro and in human cells. Genome-wide assessment of off-target activity using BLISS indicated that these variants retain high DNA-targeting specificity, which we further improved by introducing an additional non-PAM-interacting mutation. Introducing the identified PAM-interacting mutations at their corresponding positions in LbCpf1 similarly altered its PAM specificity. Together, these variants increase the targeting range of Cpf1 by approximately threefold in human coding sequences to one cleavage site per ∼11 bp.

  9. Nonparaxial and paraxial focusing of azimuthal-variant vector beams.

    Science.gov (United States)

    Gu, Bing; Cui, Yiping

    2012-07-30

    Based on the vectorial Rayleigh-Sommerfeld formulas under the weak nonparaxial approximation, we investigate the propagation behavior of a lowest-order Laguerre-Gaussian beam with azimuthal-variant states of polarization. We present the analytical expressions for the radial, azimuthal, and longitudinal components of the electric field with an arbitrary integer topological charge m focused by a nonaperturing thin lens. We illustrate the three-dimensional optical intensities, energy flux distributions, beam waists, and focal shifts of the focused azimuthal-variant vector beams under the nonparaxial and paraxial approximations.

  10. Complexity on Acute Myeloid Leukemia mRNA Transcript Variant

    Directory of Open Access Journals (Sweden)

    Carlo Cattani

    2011-01-01

    Full Text Available This paper deals with the sequence analysis of acute myeloid leukemia mRNA. Six transcript variants of mlf1 mRNA, with more than 2000 bps, are analyzed by focusing on the autocorrelation of each distribution. Through the correlation matrix, some patches and similarities are singled out and commented, with respect to similar distributions. The comparison of Kolmogorov fractal dimension will be also given in order to classify the six variants. The existence of a fractal shape, patterns, and symmetries are discussed as well.

  11. Enzyme activities and antibiotic susceptibility of colonial variants of Bacillus subtilis and Bacillus licheniformis.

    OpenAIRE

    Carlisle, G E; Falkinham, J O

    1989-01-01

    A nonmucoid colonial variant of a mucoid Bacillus subtilis strain produced less amylase activity and a transparent colonial variant of a B. licheniformis strain produced less protease activity compared with their parents. Antibiotic susceptibility patterns of the colonial variants differed, and increased resistance to beta-lactam antibiotics was correlated with increased production of extracellular beta-lactamase.

  12. Evolution of simeprevir-resistant variants over time by ultra-deep sequencing in HCV genotype 1b.

    Science.gov (United States)

    Akuta, Norio; Suzuki, Fumitaka; Sezaki, Hitomi; Suzuki, Yoshiyuki; Hosaka, Tetsuya; Kobayashi, Masahiro; Kobayashi, Mariko; Saitoh, Satoshi; Ikeda, Kenji; Kumada, Hiromitsu

    2014-08-01

    Using ultra-deep sequencing technology, the present study was designed to investigate the evolution of simeprevir-resistant variants (amino acid substitutions of aa80, aa155, aa156, and aa168 positions in HCV NS3 region) over time. In Toranomon Hospital, 18 Japanese patients infected with HCV genotype 1b, received triple therapy of simeprevir/PEG-IFN/ribavirin (DRAGON or CONCERT study). Sustained virological response rate was 67%, and that was significantly higher in patients with IL28B rs8099917 TT than in those with non-TT. Six patients, who did not achieve sustained virological response, were tested for resistant variants by ultra-deep sequencing, at the baseline, at the time of re-elevation of viral loads, and at 96 weeks after the completion of treatment. Twelve of 18 resistant variants, detected at re-elevation of viral load, were de novo resistant variants. Ten of 12 de novo resistant variants become undetectable over time, and that five of seven resistant variants, detected at baseline, persisted over time. In one patient, variants of Q80R at baseline (0.3%) increased at 96-week after the cessation of treatment (10.2%), and de novo resistant variants of D168E (0.3%) also increased at 96-week after the cessation of treatment (9.7%). In conclusion, the present study indicates that the emergence of simeprevir-resistant variants after the start of treatment could not be predicted at baseline, and the majority of de novo resistant variants become undetectable over time. Further large-scale prospective studies should be performed to investigate the clinical utility in detecting simeprevir-resistant variants. © 2014 Wiley Periodicals, Inc.

  13. Genetic variants associated with lung function

    DEFF Research Database (Denmark)

    Thyagarajan, Bharat; Wojczynski, Mary; Minster, Ryan L

    2014-01-01

    with exceptional longevity have not been identified. METHOD: We conducted a genome wide association study (GWAS) to identify novel genetic variants associated with lung function in the Long Life Family Study (LLFS) (n = 3,899). Replication was performed using data from the CHARGE/SpiroMeta consortia...

  14. Targeted deep resequencing identifies coding variants in the PEAR1 gene that play a role in platelet aggregation.

    Directory of Open Access Journals (Sweden)

    Yoonhee Kim

    Full Text Available Platelet aggregation is heritable, and genome-wide association studies have detected strong associations with a common intronic variant of the platelet endothelial aggregation receptor1 (PEAR1 gene both in African American and European American individuals. In this study, we used a sequencing approach to identify additional exonic variants in PEAR1 that may also determine variability in platelet aggregation in the GeneSTAR Study. A 0.3 Mb targeted region on chromosome 1q23.1 including the entire PEAR1 gene was Sanger sequenced in 104 subjects (45% male, 49% African American, age = 52±13 selected on the basis of hyper- and hypo- aggregation across three different agonists (collagen, epinephrine, and adenosine diphosphate. Single-variant and multi-variant burden tests for association were performed. Of the 235 variants identified through sequencing, 61 were novel, and three of these were missense variants. More rare variants (MAF<5% were noted in African Americans compared to European Americans (108 vs. 45. The common intronic GWAS-identified variant (rs12041331 demonstrated the most significant association signal in African Americans (p = 4.020×10(-4; no association was seen for additional exonic variants in this group. In contrast, multi-variant burden tests indicated that exonic variants play a more significant role in European Americans (p = 0.0099 for the collective coding variants compared to p = 0.0565 for intronic variant rs12041331. Imputation of the individual exonic variants in the rest of the GeneSTAR European American cohort (N = 1,965 supports the results noted in the sequenced discovery sample: p = 3.56×10(-4, 2.27×10(-7, 5.20×10(-5 for coding synonymous variant rs56260937 and collagen, epinephrine and adenosine diphosphate induced platelet aggregation, respectively. Sequencing approaches confirm that a common intronic variant has the strongest association with platelet aggregation in African Americans

  15. Analysis of potential protein-modifying variants in 9000 endometriosis patients and 150000 controls of European ancestry

    DEFF Research Database (Denmark)

    Sapkota, Yadav; Vivo, Immaculata De; Steinthorsdottir, Valgerdur

    2017-01-01

    -modifying variants in endometriosis using exome-array genotyping in 7164 cases and 21005 controls, and a replication set of 1840 cases and 129016 controls of European ancestry. Results in the discovery sample identified significant evidence for association with coding variants in single-variant (rs1801232-CUBN...... sufficient power, our results did not identify any protein-modifying variants (MAF > 0.01) with moderate or large effect sizes in endometriosis, although these variants may exist in non-European populations or in high-risk families. The results suggest continued discovery efforts should focus on genotyping...

  16. Structural Basis for Degenerate Recognition of Natural HIV Peptide Variants by Cytotoxic Lymphocytes

    International Nuclear Information System (INIS)

    Martinez-Hackert, E.; Anikeeva, N.; Kalams, S.; Walker, B.; Hendrickson, W.; Sykulev, Y.

    2006-01-01

    It is well established that even small changes in amino acid side chains of antigenic peptide bound to MHC protein may completely abrogate recognition of the peptide-MHC (pMHC) complex by the T-cell receptor (TCR). Often, however, several non-conservative substitutions in the peptide antigen are accommodated and do not impair its recognition by TCR. For example, a preponderance of natural sequence variants of the HIV p17 Gag-derived peptide SLYNTVATL (SL9) are recognized by cytotoxic T lymphocytes (CTL), which implies that interactions with SL9 variants are degenerate both with respect to the class I MHC molecule and with respect to TCR. Here we study the molecular basis for this degenerate recognition of SL9 variants. We show that several SL9 variants bind comparably well to soluble HLA-A2 and to a particular soluble TCR and that these variants are active in the cognate cytotoxicity assay. Natural SL9 variation is restricted by its context in the HIV p17 matrix protein, and we have used synthetic variants to explore the wider spectrum of recognition. High-resolution crystal structures of seven selected SL9 variants bound to HLA-A2 all have remarkably similar peptide conformations and side-chain dispositions outside sites of substitution. This preservation of the peptide conformation despite epitope variations suggests a mechanism for the observed degeneracy in pMHC recognition by TCR, and may contribute to the persistence of SL9-mediated immune responses in chronically infected individuals

  17. Multiple lupus-associated ITGAM variants alter Mac-1 functions on neutrophils.

    Science.gov (United States)

    Zhou, Yebin; Wu, Jianming; Kucik, Dennis F; White, Nathan B; Redden, David T; Szalai, Alexander J; Bullard, Daniel C; Edberg, Jeffrey C

    2013-11-01

    Multiple studies have demonstrated that single-nucleotide polymorphisms (SNPs) in the ITGAM locus (including the nonsynonymous SNPs rs1143679, rs1143678, and rs1143683) are associated with systemic lupus erythematosus (SLE). ITGAM encodes the protein CD11b, a subunit of the β2 integrin Mac-1. The purpose of this study was to determine the effects of ITGAM genetic variation on the biologic functions of neutrophil Mac-1. Neutrophils from ITGAM-genotyped and -sequenced healthy donors were isolated for functional studies. The phagocytic capacity of neutrophil ITGAM variants was probed with complement-coated erythrocytes, serum-treated zymosan, heat-treated zymosan, and IgG-coated erythrocytes. The adhesion capacity of ITGAM variants, in adhering to either purified intercellular adhesion molecule 1 or tumor necrosis factor α-stimulated endothelial cells, was assessed in a flow chamber. Expression levels of total CD11b and activation of CD11b were assessed by flow cytometry. Mac-1-mediated neutrophil phagocytosis, determined in cultures with 2 different complement-coated particles, was significantly reduced in individuals with nonsynonymous variant alleles of ITGAM. This reduction in phagocytosis was related to variation at either rs1143679 (in the β-propeller region) or rs1143678/rs1143683 (highly linked SNPs in the cytoplasmic/calf-1 regions). Phagocytosis mediated by Fcγ receptors was also significantly reduced in donors with variant ITGAM alleles. Similarly, firm adhesion of neutrophils was significantly reduced in individuals with variant ITGAM alleles. These functional alterations were not attributable to differences in total receptor expression or activation. The nonsynonymous ITGAM variants rs1143679 and rs1143678/rs113683 contribute to altered Mac-1 function on neutrophils. These results underscore the need to consider multiple nonsynonymous SNPs when assessing the functional consequences of ITGAM variation on immune cell processes and the risk of SLE

  18. Influence of HFE variants and cellular iron on monocyte chemoattractant protein-1

    Directory of Open Access Journals (Sweden)

    Simmons Zachary

    2009-02-01

    Full Text Available Abstract Background Polymorphisms in the MHC class 1-like gene known as HFE have been proposed as genetic modifiers of neurodegenerative diseases that include neuroinflammation as part of the disease process. Variants of HFE are relatively common in the general population and are most commonly associated with iron overload, but can promote subclinical cellular iron loading even in the absence of clinically identified disease. The effects of the variants as well as the resulting cellular iron dyshomeostasis potentially impact a number of disease-associated pathways. We tested the hypothesis that the two most common HFE variants, H63D and C282Y, would affect cellular secretion of cytokines and trophic factors. Methods We screened a panel of cytokines and trophic factors using a multiplexed immunoassay in human neuroblastoma SH-SY5Y cells expressing different variants of HFE. The influence of cellular iron secretion on the potent chemokine monocyte chemoattractant protein-1 (MCP-1 was assessed using ferric ammonium citrate and the iron chelator, desferroxamine. Additionally, an antioxidant, Trolox, and an anti-inflammatory, minocycline, were tested for their effects on MCP-1 secretion in the presence of HFE variants. Results Expression of the HFE variants altered the labile iron pool in SH-SY5Y cells. Of the panel of cytokines and trophic factors analyzed, only the release of MCP-1 was affected by the HFE variants. We further examined the relationship between iron and MCP-1 and found MCP-1 secretion tightly associated with intracellular iron status. A potential direct effect of HFE is considered because, despite having similar levels of intracellular iron, the association between HFE genotype and MCP-1 expression was different for the H63D and C282Y HFE variants. Moreover, HFE genotype was a factor in the effect of minocycline, a multifaceted antibiotic used in treating a number of neurologic conditions associated with inflammation, on MCP-1

  19. Spatially-Variant Tikhonov Regularization for Double-Difference Waveform Inversion

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Youzuo [Los Alamos National Laboratory; Huang, Lianjie [Los Alamos National Laboratory; Zhang, Zhigang [Los Alamos National Laboratory

    2011-01-01

    Double-difference waveform inversion is a potential tool for quantitative monitoring for geologic carbon storage. It jointly inverts time-lapse seismic data for changes in reservoir geophysical properties. Due to the ill-posedness of waveform inversion, it is a great challenge to obtain reservoir changes accurately and efficiently, particularly when using time-lapse seismic reflection data. Regularization techniques can be utilized to address the issue of ill-posedness. The regularization parameter controls the smoothness of inversion results. A constant regularization parameter is normally used in waveform inversion, and an optimal regularization parameter has to be selected. The resulting inversion results are a trade off among regions with different smoothness or noise levels; therefore the images are either over regularized in some regions while under regularized in the others. In this paper, we employ a spatially-variant parameter in the Tikhonov regularization scheme used in double-difference waveform tomography to improve the inversion accuracy and robustness. We compare the results obtained using a spatially-variant parameter with those obtained using a constant regularization parameter and those produced without any regularization. We observe that, utilizing a spatially-variant regularization scheme, the target regions are well reconstructed while the noise is reduced in the other regions. We show that the spatially-variant regularization scheme provides the flexibility to regularize local regions based on the a priori information without increasing computational costs and the computer memory requirement.

  20. Angiography of histopathologic variants of synovial sarcoma

    International Nuclear Information System (INIS)

    Lois, J.F.; Fischer, H.J.; Mirra, J.M.; Gomes, A.S.; California Univ., Los Angeles

    1986-01-01

    Synovial sarcomas are rare soft tissue tumors which histopathologically can be divided into monophasic, biphasic and mixed variants. As part of a protocol for intra-arterial chemotherapy 12 patients with biopsy proven synovial sarcoma underwent angiography. The angiograms on these patients were reviewed to determine whether synovial sarcomas and their variants demonstrated a characteristic angiographic appearance. Synovial sarcomas appeared angiographically as soft tissue masses which showed a fine network of tumor vessels with an inhomogeneous capillary blush. Their degree of vascularity varied according to their histopathology. Monophasic synovial sarcomas demonstrated in general a higher degree of neovascularity than the biphasic form. This finding was also suggested by histopathologic analysis of the vessels in the tumor. Although angiography did not show a distinctive vascular pattern it may be useful to evaluate tumor size and vascularity. (orig.)

  1. Two novel rare variants of APOA5 gene found in subjects with severe hypertriglyceridemia.

    Science.gov (United States)

    Pisciotta, Livia; Fresa, Raffaele; Bellocchio, Antonella; Guido, Virgilia; Priore Oliva, Claudio; Calandra, Sebastiano; Bertolini, Stefano

    2011-11-20

    Common variants of APOA5 gene affect plasma triglyceride (TG) in the population and a number of rare variants APOA5 have been reported in individuals with hypertriglyceridemia (HTG). APOA5 was analysed in 98 HTG individuals (plasma TG >9 mmol/L) in whom no mutations in LPL and APOC2 had been found. Two patients were found to be heterozygous for two novel APOA5 variants. The first variant (p.L253P) was identified in an obese male who consumed a diet rich in fat and simple sugars. He was also a carrier in trans of the common TG-raising p.S19W SNP (5*3 haplotype). The second variant (c.295-297 del GAG, p.E99 del) was found in a lean male with no life style or metabolic factors known to affect plasma TG. He was a carrier in trans of the TG-raising 5*2 haplotype and was homozygous for the rare c.1337T allele of a SNP of GCKR gene. No mutations in other genes affecting plasma TG (LMF1 and GPIHBP1) were found in these patients. These APOA5 variants, resulted to be deleterious in silico, were not found in 350 control subjects. These novel APOA5 variants predispose to HTG in combination with other genetic or nutritional factors. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. Hb F Levels in Indian Sickle Cell Patients and Association with the HBB Locus Variant rs10128556 (C>T), and the HBG XmnI (Arab-Indian) Variant.

    Science.gov (United States)

    Bhanushali, Aparna A; Himani, Kumari; Patra, Pradeep K; Das, Bibhu R

    The prevalence of sickle cell disease in India is very high. Hb F is one of the most powerful modulators of disease severity in sickle cell disease patients. It was traditionally thought that the disease is milder in Indian sickle cell disease patients predominantly due to the Arab-Indian haplotype characterized by the HBG XmnI [rs7482144 (G>A)] variant, which is associated with increased Hb F levels. In the current study, we investigated the Hb F levels in individuals with the rs10128556 (C>T) variant and also determined its linkage with the HBG XmnI variant. The present study was conducted on a cohort of 275 individuals, which consisted of 221 patients with sickle cell disease and 54 patients with sickle cell trait. Analysis of hemoglobin (Hb) fractions and variants was done on the high performance liquid chromatography (HPLC) system. Genotyping for rs10128556 was done by direct sequencing of the products. Mean Hb F levels in the sickle cell disease patients was 19.36 ± 6.79. The genotypic frequencies for rs10128556 were 82.0% (TT), 16.7% (CT) and 1.3% (CC) for sickle cell disease patients. The minor C allele resulted in 52.0% decrease in Hb F levels when homozygous and 7.0% decrease when heterozygous. The rs10128556 single nucleotide polymorphism (SNP) was in strong but not complete linkage with the HBG XmnI variant. In conclusion, the study determined for the first time the frequency and association of rs10128556 in Indian sickle cell disease patients with Hb F. It also established that it was not in complete linkage with the HBG XmnI variant in this high risk population.

  3. Identification of genomic variants putatively targeted by selection during dog domestication.

    Science.gov (United States)

    Cagan, Alex; Blass, Torsten

    2016-01-12

    Dogs [Canis lupus familiaris] were the first animal species to be domesticated and continue to occupy an important place in human societies. Recent studies have begun to reveal when and where dog domestication occurred. While much progress has been made in identifying the genetic basis of phenotypic differences between dog breeds we still know relatively little about the genetic changes underlying the phenotypes that differentiate all dogs from their wild progenitors, wolves [Canis lupus]. In particular, dogs generally show reduced aggression and fear towards humans compared to wolves. Therefore, selection for tameness was likely a necessary prerequisite for dog domestication. With the increasing availability of whole-genome sequence data it is possible to try and directly identify the genetic variants contributing to the phenotypic differences between dogs and wolves. We analyse the largest available database of genome-wide polymorphism data in a global sample of dogs 69 and wolves 7. We perform a scan to identify regions of the genome that are highly differentiated between dogs and wolves. We identify putatively functional genomic variants that are segregating or at high frequency [> = 0.75 Fst] for alternative alleles between dogs and wolves. A biological pathways analysis of the genes containing these variants suggests that there has been selection on the 'adrenaline and noradrenaline biosynthesis pathway', well known for its involvement in the fight-or-flight response. We identify 11 genes with putatively functional variants fixed for alternative alleles between dogs and wolves. The segregating variants in these genes are strong candidates for having been targets of selection during early dog domestication. We present the first genome-wide analysis of the different categories of putatively functional variants that are fixed or segregating at high frequency between a global sampling of dogs and wolves. We find evidence that selection has been strongest

  4. DIF3D-VARIANT 11.0: A Decade of Updates

    Energy Technology Data Exchange (ETDEWEB)

    Smith, M. A. [Argonne National Lab. (ANL), Argonne, IL (United States); Lewis, E. E. [Argonne National Lab. (ANL), Argonne, IL (United States); Shemon, E. R. [Argonne National Lab. (ANL), Argonne, IL (United States)

    2014-04-09

    The DIF3D code has been a workhorse of fast reactor analysis work at Argonne National Laboratory for over 30 years. In 1995, a transport option called VARIANT was added to DIF3D to improve the flux solutions for fast reactor problems. VARIANT performs nodal neutron transport calculations using PN or SPN theory in Cartesian and hexagonal two- and threedimensional geometries. Because of the computing capabilities at that time, VARIANT was restricted to 33 group P3 flux approximations with P1 scattering. Clearly computer memory capabilities have increased since then and thus large space-angle-energy approximations are possible. This manuscript serves as an update to the theory section of the original manual and details more than a decade worth of changes made to DIF3D to make DIF3D 11.0.

  5. HPV-6 Molecular Variants Association With the Development of Genital Warts in Men: The HIM Study.

    Science.gov (United States)

    Flores-Díaz, Ema; Sereday, Karen A; Ferreira, Silvaneide; Sirak, Bradley; Sobrinho, João Simão; Baggio, Maria Luiza; Galan, Lenice; Silva, Roberto C; Lazcano-Ponce, Eduardo; Giuliano, Anna R; Villa, Luisa L; Sichero, Laura

    2017-02-15

    Human papillomavirus type 6 (HPV-6) and HPV-11 are the etiological agents of approximately 90% of genital warts (GWs). The impact of HPV-6 genetic heterogeneity on persistence and progression to GWs remains undetermined. HPV Infection in Men (HIM) Study participants who had HPV-6 genital swabs and/or GWs preceded by a viable normal genital swab were analyzed. Variants characterization was performed by polymerase chain reaction sequencing and samples classified within lineages (A, B) and sublineages (B1, B2, B3, B4, B5). Country- and age-specific analyses were conducted for individual variants; odds ratios and 95% confidence intervals for the risk of GWs according to HPV-6 variants were calculated. B3 variants were most prevalent. HPV-6 variants distribution differed between countries and case status. HPV-6 B1 variants prevalence was increased in GWs and genital swabs of cases compared to controls. There was difference in B1 and B3 variants detection in GW and the preceding genital swab. We observed significant association of HPV-6 B1 variants detection with GW development. HPV-6 B1 variants are more prevalent in genital swabs that precede GW development, and confer an increased risk for GW. Further research is warranted to understand the possible involvement of B1 variants in the progression to clinically relevant lesions. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  6. Human activated protein C variants in a rat model of arterial thrombosis

    Directory of Open Access Journals (Sweden)

    Dahlbäck Björn

    2008-10-01

    Full Text Available Abstract Background Activated protein C (APC inhibits coagulation by degrading activated factor V (FVa and factor VIII (FVIIIa, protein S (PS functioning as a cofactor to APC. Methods By mutagenesis of the vitamin K-dependent Gla domain of APC, we have recently created an APC variant having enhanced anticoagulant activity due to increased affinity for negatively charged phospholipid membranes. In the present study, the potential antithrombotic effects of this APC variant, and of a variant APC that is additionally mutated in the serine protease domain, have been evaluated in a blind randomized study in a rat model of arterial thrombosis. In this model, we have previously found the combination of bovine APC and PS to be highly antithrombotic. Four treatment groups each containing 10 rats were, in a blind random fashion, given intravenous bolus injections of wild-type or mutant variants of APC (0.8 mg/kg together with human PS (0.6 mg/kg or human PS (0.6 mg/kg alone. A control group with 20 animals where given vehicle only. Results A trend to increased patency rates was noted in a group receiving one of the APC variants, but it did not reach statistical significance. Conclusion In conclusion, administration of human APC variants having enhanced anticoagulant efficacy together with human PS in a rat model of arterial thrombosis did not give an efficient antithrombotic effect. The lack of effect may be due to species-specific differences between the human protein C system and the rat hemostatic system.

  7. MYO7A and USH2A gene sequence variants in Italian patients with Usher syndrome.

    Science.gov (United States)

    Sodi, Andrea; Mariottini, Alessandro; Passerini, Ilaria; Murro, Vittoria; Tachyla, Iryna; Bianchi, Benedetta; Menchini, Ugo; Torricelli, Francesca

    2014-01-01

    To analyze the spectrum of sequence variants in the MYO7A and USH2A genes in a group of Italian patients affected by Usher syndrome (USH). Thirty-six Italian patients with a diagnosis of USH were recruited. They received a standard ophthalmologic examination, visual field testing, optical coherence tomography (OCT) scan, and electrophysiological tests. Fluorescein angiography and fundus autofluorescence imaging were performed in selected cases. All the patients underwent an audiologic examination for the 0.25-8,000 Hz frequencies. Vestibular function was evaluated with specific tests. DNA samples were analyzed for sequence variants of the MYO7A gene (for USH1) and the USH2A gene (for USH2) with direct sequencing techniques. A few patients were analyzed for both genes. In the MYO7A gene, ten missense variants were found; three patients were compound heterozygous, and two were homozygous. Thirty-four USH2A gene variants were detected, including eight missense variants, nine nonsense variants, six splicing variants, and 11 duplications/deletions; 19 patients were compound heterozygous, and three were homozygous. Four MYO7A and 17 USH2A variants have already been described in the literature. Among the novel mutations there are four USH2A large deletions, detected with multiplex ligation dependent probe amplification (MLPA) technology. Two potentially pathogenic variants were found in 27 patients (75%). Affected patients showed variable clinical pictures without a clear genotype-phenotype correlation. Ten variants in the MYO7A gene and 34 variants in the USH2A gene were detected in Italian patients with USH at a high detection rate. A selective analysis of these genes may be valuable for molecular analysis, combining diagnostic efficiency with little time wastage and less resource consumption.

  8. Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

    Science.gov (United States)

    Milne, Roger L; Kuchenbaecker, Karoline B; Michailidou, Kyriaki; Beesley, Jonathan; Kar, Siddhartha; Lindström, Sara; Hui, Shirley; Lemaçon, Audrey; Soucy, Penny; Dennis, Joe; Jiang, Xia; Rostamianfar, Asha; Finucane, Hilary; Bolla, Manjeet K; McGuffog, Lesley; Wang, Qin; Aalfs, Cora M; Adams, Marcia; Adlard, Julian; Agata, Simona; Ahmed, Shahana; Ahsan, Habibul; Aittomäki, Kristiina; Al-Ejeh, Fares; Allen, Jamie; Ambrosone, Christine B; Amos, Christopher I; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Arndt, Volker; Arnold, Norbert; Aronson, Kristan J; Auber, Bernd; Auer, Paul L; Ausems, Margreet G E M; Azzollini, Jacopo; Bacot, François; Balmaña, Judith; Barile, Monica; Barjhoux, Laure; Barkardottir, Rosa B; Barrdahl, Myrto; Barnes, Daniel; Barrowdale, Daniel; Baynes, Caroline; Beckmann, Matthias W; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Bignon, Yves-Jean; Blazer, Kathleen R; Blok, Marinus J; Blomqvist, Carl; Blot, William; Bobolis, Kristie; Boeckx, Bram; Bogdanova, Natalia V; Bojesen, Anders; Bojesen, Stig E; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Bozsik, Aniko; Bradbury, Angela R; Brand, Judith S; Brauch, Hiltrud; Brenner, Hermann; Bressac-de Paillerets, Brigitte; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Brunet, Joan; Brüning, Thomas; Burwinkel, Barbara; Buys, Saundra S; Byun, Jinyoung; Cai, Qiuyin; Caldés, Trinidad; Caligo, Maria A; Campbell, Ian; Canzian, Federico; Caron, Olivier; Carracedo, Angel; Carter, Brian D; Castelao, J Esteban; Castera, Laurent; Caux-Moncoutier, Virginie; Chan, Salina B; Chang-Claude, Jenny; Chanock, Stephen J; Chen, Xiaoqing; Cheng, Ting-Yuan David; Chiquette, Jocelyne; Christiansen, Hans; Claes, Kathleen B M; Clarke, Christine L; Conner, Thomas; Conroy, Don M; Cook, Jackie; Cordina-Duverger, Emilie; Cornelissen, Sten; Coupier, Isabelle; Cox, Angela; Cox, David G; Cross, Simon S; Cuk, Katarina; Cunningham, Julie M; Czene, Kamila; Daly, Mary B; Damiola, Francesca; Darabi, Hatef; Davidson, Rosemarie; De Leeneer, Kim; Devilee, Peter; Dicks, Ed; Diez, Orland; Ding, Yuan Chun; Ditsch, Nina; Doheny, Kimberly F; Domchek, Susan M; Dorfling, Cecilia M; Dörk, Thilo; dos-Santos-Silva, Isabel; Dubois, Stéphane; Dugué, Pierre-Antoine; Dumont, Martine; Dunning, Alison M; Durcan, Lorraine; Dwek, Miriam; Dworniczak, Bernd; Eccles, Diana; Eeles, Ros; Ehrencrona, Hans; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B; Engel, Christoph; Eriksson, Mikael; Fachal, Laura; Faivre, Laurence; Fasching, Peter A; Faust, Ulrike; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Foulkes, William D; Friedman, Eitan; Fritschi, Lin; Frost, Debra; Gabrielson, Marike; Gaddam, Pragna; Gammon, Marilie D; Ganz, Patricia A; Gapstur, Susan M; Garber, Judy; Garcia-Barberan, Vanesa; García-Sáenz, José A; Gaudet, Mia M; Gauthier-Villars, Marion; Gehrig, Andrea; Georgoulias, Vassilios; Gerdes, Anne-Marie; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Goodfellow, Paul; Greene, Mark H; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Gschwantler-Kaulich, Daphne; Guénel, Pascal; Guo, Qi; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A; Håkansson, Niclas; Hallberg, Emily; Hamann, Ute; Hamel, Nathalie; Hankinson, Susan; Hansen, Thomas V O; Harrington, Patricia; Hart, Steven N; Hartikainen, Jaana M; Healey, Catherine S; Hein, Alexander; Helbig, Sonja; Henderson, Alex; Heyworth, Jane; Hicks, Belynda; Hillemanns, Peter; Hodgson, Shirley; Hogervorst, Frans B; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Bob; Hopper, John L; Hu, Chunling; Huang, Guanmengqian; Hulick, Peter J; Humphreys, Keith; Hunter, David J; Imyanitov, Evgeny N; Isaacs, Claudine; Iwasaki, Motoki; Izatt, Louise; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Janni, Wolfgang; Jensen, Uffe Birk; John, Esther M; Johnson, Nichola; Jones, Kristine; Jones, Michael; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Kabisch, Maria; Kaczmarek, Katarzyna; Kang, Daehee; Kast, Karin; Keeman, Renske; Kerin, Michael J; Kets, Carolien M; Keupers, Machteld; Khan, Sofia; Khusnutdinova, Elza; Kiiski, Johanna I; Kim, Sung-Won; Knight, Julia A; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela N; Kruse, Torben A; Kwong, Ava; Lænkholm, Anne-Vibeke; Laitman, Yael; Lalloo, Fiona; Lambrechts, Diether; Landsman, Keren; Lasset, Christine; Lazaro, Conxi; Le Marchand, Loic; Lecarpentier, Julie; Lee, Andrew; Lee, Eunjung; Lee, Jong Won; Lee, Min Hyuk; Lejbkowicz, Flavio; Lesueur, Fabienne; Li, Jingmei; Lilyquist, Jenna; Lincoln, Anne; Lindblom, Annika; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Long, Jirong; Loud, Jennifer T; Lubinski, Jan; Luccarini, Craig; Lush, Michael; MacInnis, Robert J; Maishman, Tom; Makalic, Enes; Kostovska, Ivana Maleva; Malone, Kathleen E; Manoukian, Siranoush; Manson, JoAnn E; Margolin, Sara; Martens, John W M; Martinez, Maria Elena; Matsuo, Keitaro; Mavroudis, Dimitrios; Mazoyer, Sylvie; McLean, Catriona; Meijers-Heijboer, Hanne; Menéndez, Primitiva; Meyer, Jeffery; Miao, Hui; Miller, Austin; Miller, Nicola; Mitchell, Gillian; Montagna, Marco; Muir, Kenneth; Mulligan, Anna Marie; Mulot, Claire; Nadesan, Sue; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nevelsteen, Ines; Niederacher, Dieter; Nielsen, Sune F; Nordestgaard, Børge G; Norman, Aaron; Nussbaum, Robert L; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Olswold, Curtis; Ong, Kai-ren; Oosterwijk, Jan C; Orr, Nick; Osorio, Ana; Pankratz, V Shane; Papi, Laura; Park-Simon, Tjoung-Won; Paulsson-Karlsson, Ylva; Lloyd, Rachel; Pedersen, Inge Søkilde; Peissel, Bernard; Peixoto, Ana; Perez, Jose I A; Peterlongo, Paolo; Peto, Julian; Pfeiler, Georg; Phelan, Catherine M; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Poppe, Bruce; Porteous, Mary E; Prentice, Ross; Presneau, Nadege; Prokofieva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rennert, Hedy S; Rhenius, Valerie; Rhiem, Kerstin; Richardson, Andrea; Rodriguez, Gustavo C; Romero, Atocha; Romm, Jane; Rookus, Matti A; Rudolph, Anja; Ruediger, Thomas; Saloustros, Emmanouil; Sanders, Joyce; Sandler, Dale P; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Daniel F; Schoemaker, Minouk J; Schumacher, Fredrick; Schürmann, Peter; Schwentner, Lukas; Scott, Christopher; Scott, Rodney J; Seal, Sheila; Senter, Leigha; Seynaeve, Caroline; Shah, Mitul; Sharma, Priyanka; Shen, Chen-Yang; Sheng, Xin; Shimelis, Hermela; Shrubsole, Martha J; Shu, Xiao-Ou; Side, Lucy E; Singer, Christian F; Sohn, Christof; Southey, Melissa C; Spinelli, John J; Spurdle, Amanda B; Stegmaier, Christa; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Surowy, Harald; Sutter, Christian; Swerdlow, Anthony; Szabo, Csilla I; Tamimi, Rulla M; Tan, Yen Y; Taylor, Jack A; Tejada, Maria-Isabel; Tengström, Maria; Teo, Soo H; Terry, Mary B; Tessier, Daniel C; Teulé, Alex; Thöne, Kathrin; Thull, Darcy L; Tibiletti, Maria Grazia; Tihomirova, Laima; Tischkowitz, Marc; Toland, Amanda E; Tollenaar, Rob A E M; Tomlinson, Ian; Tong, Ling; Torres, Diana; Tranchant, Martine; Truong, Thérèse; Tucker, Kathy; Tung, Nadine; Tyrer, Jonathan; Ulmer, Hans-Ulrich; Vachon, Celine; van Asperen, Christi J; Van Den Berg, David; van den Ouweland, Ans M W; van Rensburg, Elizabeth J; Varesco, Liliana; Varon-Mateeva, Raymonda; Vega, Ana; Viel, Alessandra; Vijai, Joseph; Vincent, Daniel; Vollenweider, Jason; Walker, Lisa; Wang, Zhaoming; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Weinberg, Clarice R; Weitzel, Jeffrey N; Wendt, Camilla; Wesseling, Jelle; Whittemore, Alice S; Wijnen, Juul T; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Wu, Anna H; Xia, Lucy; Yang, Xiaohong R; Yannoukakos, Drakoulis; Zaffaroni, Daniela; Zheng, Wei; Zhu, Bin; Ziogas, Argyrios; Ziv, Elad; Zorn, Kristin K; Gago-Dominguez, Manuela; Mannermaa, Arto; Olsson, Håkan; Teixeira, Manuel R; Stone, Jennifer; Offit, Kenneth; Ottini, Laura; Park, Sue K; Thomassen, Mads; Hall, Per; Meindl, Alfons; Schmutzler, Rita K; Droit, Arnaud; Bader, Gary D; Pharoah, Paul D P; Couch, Fergus J; Easton, Douglas F; Kraft, Peter; Chenevix-Trench, Georgia; García-Closas, Montserrat; Schmidt, Marjanka K; Antoniou, Antonis C; Simard, Jacques

    2018-01-01

    Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10−8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 14% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer. PMID:29058716

  9. Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease.

    Science.gov (United States)

    Lubbe, S J; Escott-Price, V; Brice, A; Gasser, T; Pittman, A M; Bras, J; Hardy, J; Heutink, P; Wood, N M; Singleton, A B; Grosset, D G; Carroll, C B; Law, M H; Demenais, F; Iles, M M; Bishop, D T; Newton-Bishop, J; Williams, N M; Morris, H R

    2016-12-01

    A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  10. Expanding the range of ZNF804A variants conferring risk of psychosis

    NARCIS (Netherlands)

    Steinberg, S.; Mors, O.; Borglum, A.D.; Gustafsson, O.; Werge, T.; Mortensen, P.B.; Andreassen, O.A.; Sigurdsson, E.; Thorgeirsson, T.E.; Bottcher, Y.; Olason, P.; Ophoff, R.A.; Cichon, S.; Gudjonsdottir, I.H.; Pietilainen, O.P.H.; Nyegaard, M.; Tuulio-Henriksson, A.; Ingason, A.; Hansen, T.; Athanasiu, L.; Suvisaari, J.; Lonnqvist, J.; Paunio, T.; Hartmann, A.; Jurgens, G.; Nordentoft, M.; Hougaard, D.; Norgaard-Pedersen, B.; Breuer, R.; Moller, H.J.; Giegling, I.; Glenthoj, B.; Rasmussen, H.B.; Mattheisen, M.; Bitter, I.; Rethelyi, J.M.; Sigmundsson, T.; Fossdal, R.; Thorsteinsdottir, U.; Ruggeri, M.; Tosato, S.; Strengman, E.; Kiemeney, L.A.L.M.; Melle, I.; Djurovic, S.; Abramova, L.; Kaleda, V.; Walshe, M.; Bramon, E.; Vassos, E.; Li, T.; Fraser, G.; Walker, N.; Toulopoulou, T.; Yoon, J.; Freimer, N.B.; Cantor, R.M.; Murray, R.; Kong, A.; Golimbet, V.; Jonsson, E.G.; Terenius, L.; Agartz, I.; Petursson, H.; Nothen, Markus; Rietschel, M.; Peltonen, L.; Rujescu, D.; Collier, D.A.; Stefansson, H.; St Clair, D.; Stefansson, K.

    2011-01-01

    A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 x 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very

  11. Expanding the range of ZNF804A variants conferring risk of psychosis

    NARCIS (Netherlands)

    Steinberg, S.; Mors, O.; Børglum, A. D.; Gustafsson, O.; Werge, T.; Mortensen, P. B.; Andreassen, O. A.; Sigurdsson, E.; Thorgeirsson, T. E.; Böttcher, Y.; Olason, P.; Ophoff, R. A.; Cichon, S.; Gudjonsdottir, I. H.; Pietiläinen, O. P. H.; Nyegaard, M.; Tuulio-Henriksson, A.; Ingason, A.; Hansen, T.; Athanasiu, L.; Suvisaari, J.; Lonnqvist, J.; Paunio, T.; Hartmann, A.; Jürgens, G.; Nordentoft, M.; Hougaard, D.; Norgaard-Pedersen, B.; Breuer, R.; Möller, H.-J.; Giegling, I.; Glenthøj, B.; Rasmussen, H. B.; Mattheisen, M.; Bitter, I.; Réthelyi, J. M.; Sigmundsson, T.; Fossdal, R.; Thorsteinsdottir, U.; Ruggeri, M.; Tosato, S.; Strengman, E.; Kiemeney, L. A.; Melle, I.; Djurovic, S.; Abramova, L.; Kaleda, V.; Walshe, M.; Linszen, Don H.; de Haan, Lieuwe

    2011-01-01

    A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P <5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very

  12. The UK10K project identifies rare variants in health and disease

    DEFF Research Database (Denmark)

    Walter, Klaudia; Min, Josine L.; Huang, Jie

    2015-01-01

    -marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive...

  13. Rare variants in ischemic stroke: an exome pilot study.

    Directory of Open Access Journals (Sweden)

    John W Cole

    Full Text Available The genetic architecture of ischemic stroke is complex and is likely to include rare or low frequency variants with high penetrance and large effect sizes. Such variants are likely to provide important insights into disease pathogenesis compared to common variants with small effect sizes. Because a significant portion of human functional variation may derive from the protein-coding portion of genes we undertook a pilot study to identify variation across the human exome (i.e., the coding exons across the entire human genome in 10 ischemic stroke cases. Our efforts focused on evaluating the feasibility and identifying the difficulties in this type of research as it applies to ischemic stroke. The cases included 8 African-Americans and 2 Caucasians selected on the basis of similar stroke subtypes and by implementing a case selection algorithm that emphasized the genetic contribution of stroke risk. Following construction of paired-end sequencing libraries, all predicted human exons in each sample were captured and sequenced. Sequencing generated an average of 25.5 million read pairs (75 bp×2 and 3.8 Gbp per sample. After passing quality filters, screening the exomes against dbSNP demonstrated an average of 2839 novel SNPs among African-Americans and 1105 among Caucasians. In an aggregate analysis, 48 genes were identified to have at least one rare variant across all stroke cases. One gene, CSN3, identified by screening our prior GWAS results in conjunction with our exome results, was found to contain an interesting coding polymorphism as well as containing excess rare variation as compared with the other genes evaluated. In conclusion, while rare coding variants may predispose to the risk of ischemic stroke, this fact has yet to be definitively proven. Our study demonstrates the complexities of such research and highlights that while exome data can be obtained, the optimal analytical methods have yet to be determined.

  14. A guide for functional analysis of BRCA1 variants of uncertain significance

    DEFF Research Database (Denmark)

    Millot, Gaël A; Carvalho, Marcelo A; Caputo, Sandrine M

    2012-01-01

    of these variants, the effect on protein function is unknown making it difficult to infer the consequences on risks of breast and ovarian cancers. Thus, many individuals undergoing genetic testing for BRCA1 mutations receive test results reporting a variant of uncertain clinical significance (VUS), leading...... to issues in risk assessment, counseling, and preventive care. Here, we describe functional assays for BRCA1 to directly or indirectly assess the impact of a variant on protein conformation or function and how these results can be used to complement genetic data to classify a VUS as to its clinical...

  15. Variants of social-economic and energy development of Bulgaria up to 2010

    International Nuclear Information System (INIS)

    Tsvetanov, P.

    1990-01-01

    The development variants are formulated as the second stage of a procedure of energy-economy interrelations dynamics study, the other two stages being the scenarios description and the analysis of the development variants. This stage consists of interactive studies with the complex model of the economic developments (CMED), the model of the energy demand (MED) and the energy supplies model (ENERGO). The chapter presents a considerable in its depth and scope description of the energy consumption system developments, according to the alternative social economic and technological policies and also to the studies on the energy complex structure variants and the national energy balance. The economic development variants comprise 25 economic branch structures according to 6 basic economic indices. The energy demand development variants embrace the energy consumption system (including final energy demand, final electrical power demand of the industrial, transportation, household and services sectors), the energy supply system (fuel production and energy conversion) demand and the total energy demands of the country. The dynamics of the final energy demand is considered by 14 types of energy carriers. In addition a draft study on the implementation of gas turbine and combined cycle power plants in the electricity and heat production of the country is presented. 16 refs., 28 figs., 25 tab. (R.Ts.)

  16. A dominant-negative mutant inhibits multiple prion variants through a common mechanism.

    Directory of Open Access Journals (Sweden)

    Fen Pei

    2017-10-01

    Full Text Available Prions adopt alternative, self-replicating protein conformations and thereby determine novel phenotypes that are often irreversible. Nevertheless, dominant-negative prion mutants can revert phenotypes associated with some conformations. These observations suggest that, while intervention is possible, distinct inhibitors must be developed to overcome the conformational plasticity of prions. To understand the basis of this specificity, we determined the impact of the G58D mutant of the Sup35 prion on three of its conformational variants, which form amyloids in S. cerevisiae. G58D had been previously proposed to have unique effects on these variants, but our studies suggest a common mechanism. All variants, including those reported to be resistant, are inhibited by G58D but at distinct doses. G58D lowers the kinetic stability of the associated amyloid, enhancing its fragmentation by molecular chaperones, promoting Sup35 resolubilization, and leading to amyloid clearance particularly in daughter cells. Reducing the availability or activity of the chaperone Hsp104, even transiently, reverses curing. Thus, the specificity of inhibition is determined by the sensitivity of variants to the mutant dosage rather than mode of action, challenging the view that a unique inhibitor must be developed to combat each variant.

  17. Shift-Variant Multidimensional Systems.

    Science.gov (United States)

    1985-05-29

    x,y;u,v) is the system response at (x,y) to an unit impulse applied at (u,v). The presence of additive noise in the preceding input-output model of a...space model developed works very effi- ciently to deblur images affected by 2-D linear shift- varying blurs, its use, in presence of noise needs to be...causal linear shift-variant (LSV) system, whose impulse res- ponse is a K-th order degenerate sequence, a K-th order state-space model was obtained

  18. An Alternate Splicing Variant of the Human Telomerase Catalytic Subunit Inhibits Telomerase Activity

    Directory of Open Access Journals (Sweden)

    Xiaoming Yi

    2000-09-01

    Full Text Available Telomerase, a cellular reverse transcriptase, adds telomeric repeats to chromosome ends. In normal human somatic cells, telomerase is repressed and telomeres progressively shorten, leading to proliferative senescence. Introduction of the telomerase (hTERT cDNA is sufficient to produce telomerase activity and immortalize normal human cells, suggesting that the repression of telomerase activity is transcriptional. The telomerase transcript has been shown to have at least six alternate splicing sites (four insertion sites and two deletion sites, and variants containing both or either of the deletion sites are present during development and in a panel of cancer cell lines we surveyed. One deletion (β site and all four insertions cause premature translation terminations, whereas the other deletion (α site is 36 by and lies within reverse transcriptase (RT motif A, suggesting that this deletion variant may be a candidate as a dominant-negative inhibitor of telomerase. We have cloned three alternately spliced hTERT variants that contain the α,β or both α and,β deletion sites. These alternate splicing variants along with empty vector and wild-type hTERT were introduced into normal human fibroblasts and several telomerase-positive immortal and tumor cell lines. Expression of the α site deletion variant (hTERT α− construct was confirmed by Western blotting. We found that none of the three alternate splicing variants reconstitutes telomerase activity in fibroblasts. However, hTERT α− inhibits telomerase activities in telomerase-positive cells, causes telomere shortening and eventually cell death. This alternately spliced dominant-negative variant may be important in understanding telomerase regulation during development, differentiation and in cancer progression.

  19. Cellobiohydrolase I gene and improved variants

    Science.gov (United States)

    Adney, William S [Golden, CO; Decker, Stephen R [Berthoud, CO; Mc Carter, Suzanne [San Carlos, CA; Baker, John O [Golden, CO; Nieves, Raphael [Lakewood, CO; Himmel, Michael E [Littleton, CO; Vinzant, Todd B [Golden, CO

    2008-05-20

    The disclosure provides a method for preparing an active exoglucanase in a heterologous host of eukaryotic origin. The method includes mutagenesis to reduce glycosylation of the exoglucanase when expressed in a heterologous host. It is further disclosed a method to produce variant cellobiohydrolase that is stable at high temperature through mutagenesis.

  20. Coagulation factor VII variants resistant to inhibitory antibodies.

    Science.gov (United States)

    Branchini, Alessio; Baroni, Marcello; Pfeiffer, Caroline; Batorova, Angelika; Giansily-Blaizot, Muriel; Schved, Jean F; Mariani, Guglielmo; Bernardi, Francesco; Pinotti, Mirko

    2014-11-01

    Replacement therapy is currently used to prevent and treat bleeding episodes in coagulation factor deficiencies. However, structural differences between the endogenous and therapeutic proteins might increase the risk for immune complications. This study was aimed at identifying factor (F)VII variants resistant to inhibitory antibodies developed after treatment with recombinant activated factor VII (rFVIIa) in a FVII-deficient patient homozygous for the p.A354V-p.P464Hfs mutation, which predicts trace levels of an elongated FVII variant in plasma. We performed fluorescent bead-based binding, ELISA-based competition as well as fluorogenic functional (activated FX and thrombin generation) assays in plasma and with recombinant proteins. We found that antibodies displayed higher affinity for the active than for the zymogen FVII (half-maximal binding at 0.54 ± 0.04 and 0.78 ± 0.07 BU/ml, respectively), and inhibited the coagulation initiation phase with a second-order kinetics. Isotypic analysis showed a polyclonal response with a large predominance of IgG1. We hypothesised that structural differences in the carboxyl-terminus between the inherited FVII and the therapeutic molecules contributed to the immune response. Intriguingly, a naturally-occurring, poorly secreted and 5-residue truncated FVII (FVII-462X) escaped inhibition. Among a series of truncated rFVII molecules, we identified a well-secreted and catalytically competent variant (rFVII-464X) with reduced binding to antibodies (half-maximal binding at 0.198 ± 0.003 BU/ml) as compared to the rFVII-wt (0.032 ± 0.002 BU/ml), which led to a 40-time reduced inhibition in activated FX generation assays. Taken together our results provide a paradigmatic example of mutation-related inhibitory antibodies, strongly support the FVII carboxyl-terminus as their main target and identify inhibitor-resistant FVII variants.

  1. [Homozygous ectonucleotide pyrophosphatase/phosphodiesterase 1 variants in a girl with hypophosphatemic rickets and literature review].

    Science.gov (United States)

    Liu, Z Q; Chen, X B; Song, F Y; Gao, K; Qiu, M F; Qian, Y; Du, M

    2017-11-02

    Objective: To investigate the clinical features and genetic characteristics of patients with ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene variants. Method: The clinical data of a patient with ENPP1 homozygous variants from Capital Institute of Pediatrics was collected, the related literature was searched from China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, National Center from Biotechnology Information and PubMed by using search term "ENPP1" , "hypophosphatemic rickets" . The literature retrieval was confined from 1980 to February 2017. The clinical manifestations, bone metabolism examinations, X-RAY and genotypes were reviewed. Result: Our patient was an 11 years old girl, with 7 years history of lower limb malformation. She showed significant valgus deformity of the knee (genu valgum). Metabolic examination revealed reduced level of plasma phosphate (0.86 mmol/L), a normal level of plasma calcium (2.30 mmol/L) and an elevated alkaline phosphatase level of 688 IU/L. The calcium-phosphorus product was 25.9. A homozygous nonsense variants of ENPP1 gene, c.783C>G (p.Tyr261X) in exon 7 was identified in the patient. Both parents were heterozygous carriers. Literature review identified 3 Chinese patients from one publication and 17 cases from twenty one publications around the world. None of the patients was found PHEX variants which is the most common variants among hypophosphatemic rickets patients. The disease onset age was 11 months to 10 years. Eight patients had short stature, five patients had the history of generalized arterial calcification of infancy. Four suffered from deafness, three showed localized calcifications of arteries, three patients manifested pseudoxanthoma elasticum and two suffered from ossification of posterior longitudinal ligament. Nine missense variants, six splicing variants and 4 nonsense variants were reported among these twenty patients. c.783C>G was found in two Chinese patients

  2. Distribution and medical impact of loss-of-function variants in the Finnish founder population.

    Directory of Open Access Journals (Sweden)

    Elaine T Lim

    2014-07-01

    Full Text Available Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5% variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10⁻⁸ including splice variants in LPA that lowered plasma lipoprotein(a levels (P = 1.5×10⁻¹¹⁷. Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10⁻⁴, demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health

  3. Two novel haemoglobin variants that affect haemoglobin A1c measurement by ion-exchange chromatography

    NARCIS (Netherlands)

    Bots, Michael; Stroobants, An K.; Delzenne, Barend; Soeters, Maarten R.; de Vries, Johan E.; Weykamp, Cas W.; Norg, Roelf J. C.; Veldthuis, Martijn; van Zwieten, Rob

    2015-01-01

    Haemoglobin (Hb) variants are well-known factors interfering with accurate HbA1c testing. This report describes two novel Hb variants leading to inappropriate quantification of HbA1c by ion-exchange chromatography. Glycated forms of novel Hb variants were recognised in the blood of two patients with

  4. Self accommodation morphology of martensite variants in Zr-2.5wt%Nb alloy

    International Nuclear Information System (INIS)

    Srivastava, D.; Madangopal, K.; Banerjee, S.; Ranganathan, S.

    1993-01-01

    The role of self accommodation of the different martensite variants in controlling the morphologies of the Zr-2.5wt%Nb alloy martensite has been examined. Three distinct types of grouping of martensite variants have been found to be predominantly present. Crystallographic descriptions of these groups have been provided and the degrees of self accommodation for these have been estimated and compared with those corresponding to other possible variant groupings around the symmetry axes of the parent phase. The frequently observed 3-variant group, which shows an indentation mark morphology when viewed along β directions in the transmission electron microscope, has been seen to have the highest degree of self accommodation amongst the cases considered. Based on the observations made, a growth sequence leading to the formation of the final martensitic structure has been proposed

  5. Carcinoma-risk variant of EBNA1 deregulates Epstein-Barr Virus episomal latency.

    Science.gov (United States)

    Dheekollu, Jayaraju; Malecka, Kimberly; Wiedmer, Andreas; Delecluse, Henri-Jacques; Chiang, Alan K S; Altieri, Dario C; Messick, Troy E; Lieberman, Paul M

    2017-01-31

    Epstein-Barr Virus (EBV) latent infection is a causative co-factor for endemic Nasopharyngeal Carcinoma (NPC). NPC-associated variants have been identified in EBV-encoded nuclear antigen EBNA1. Here, we solve the X-ray crystal structure of an NPC-derived EBNA1 DNA binding domain (DBD) and show that variant amino acids are found on the surface away from the DNA binding interface. We show that NPC-derived EBNA1 is compromised for DNA replication and episome maintenance functions. Recombinant virus containing the NPC EBNA1 DBD are impaired in their ability to immortalize primary B-lymphocytes and suppress lytic transcription during early stages of B-cell infection. We identify Survivin as a host protein deficiently bound by the NPC variant of EBNA1 and show that Survivin depletion compromises EBV episome maintenance in multiple cell types. We propose that endemic variants of EBNA1 play a significant role in EBV-driven carcinogenesis by altering key regulatory interactions that destabilize latent infection.

  6. [Clinical and morphological variants of diverticular disease in colon].

    Science.gov (United States)

    Levchenko, S V; Lazebnik, L B; Potapova, V B; Rogozina, V A

    2013-01-01

    Our own results of two-stage research are presented in the article. The first stage contains the retrospective analysis of 3682 X-ray examining of large bowel which were conducted in 2002-2004 to define the structure of colon disease and to determine gender differences. The second stage is prospective research which took place from 2003 to 2012 and 486 patients with diverticular disease were regularly observed. Following parameters were estimated: dynamics of complaints, life quality, clinical symptoms. Multiple X-ray and endoscopic examining were done with estimation of quantity and size of diverticula, changes of colon mucosa, comparison of X-ray and endoscopic methods in prognosis of complications. Two basic clinical morphological variants of diverticular disease (DD) of colon are made out as a result of our research. There are IBD-like and DD with ischemic component. The variants differ by pain characteristics, presence of accompanying diseases, life quality parameters and description of colon mucosa morphological research. We suppose that different ethiopathogenetic factors of development of both variants mentioned above influence the disease prognosis and selection of treatment.

  7. Functional non-synonymous variants of ABCG2 and gout risk.

    Science.gov (United States)

    Stiburkova, Blanka; Pavelcova, Katerina; Zavada, Jakub; Petru, Lenka; Simek, Pavel; Cepek, Pavel; Pavlikova, Marketa; Matsuo, Hirotaka; Merriman, Tony R; Pavelka, Karel

    2017-11-01

    Common dysfunctional variants of ATP binding cassette subfamily G member 2 (Junior blood group) (ABCG2), a high-capacity urate transporter gene, that result in decreased urate excretion are major causes of hyperuricemia and gout. In the present study, our objective was to determine the frequency and effect on gout of common and rare non-synonymous and other functional allelic variants in the ABCG2 gene. The main cohort recruited from the Czech Republic consisted of 145 gout patients; 115 normouricaemic controls were used for comparison. We amplified, directly sequenced and analysed 15 ABCG2 exons. The associations between genetic variants and clinical phenotype were analysed using the t-test, Fisher's exact test and a logistic and linear regression approach. Data from a New Zealand Polynesian sample set and the UK Biobank were included for the p.V12M analysis. In the ABCG2 gene, 18 intronic (one dysfunctional splicing) and 11 exonic variants were detected: 9 were non-synonymous (2 common, 7 rare including 1 novel), namely p.V12M, p.Q141K, p.R147W, p.T153M, p.F373C, p.T434M, p.S476P, p.D620N and p.K360del. The p.Q141K (rs2231142) variant had a significantly higher minor allele frequency (0.23) in the gout patients compared with the European-origin population (0.09) and was significantly more common among gout patients than among normouricaemic controls (odds ratio = 3.26, P gout (42 vs 48 years, P = 0.0143) and a greater likelihood of a familial history of gout (41% vs 27%, odds ratio = 1.96, P = 0.053). In a meta-analysis p.V12M exerted a protective effect from gout (P gout. Non-synonymous allelic variants of ABCG2 had a significant effect on earlier onset of gout and the presence of a familial gout history. ABCG2 should thus be considered a common and significant risk factor for gout. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  8. Rapid screening for targeted genetic variants via high-resolution melting curve analysis.

    Science.gov (United States)

    Chambliss, Allison B; Resnick, Molly; Petrides, Athena K; Clarke, William A; Marzinke, Mark A

    2017-03-01

    Current methods for the detection of single nucleotide polymorphisms (SNPs) associated with aberrant drug-metabolizing enzyme function are hindered by long turnaround times and specialized techniques and instrumentation. In this study, we describe the development and validation of a high-resolution melting (HRM) curve assay for the rapid screening of variant genotypes for targeted genetic polymorphisms in the cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A5. Sequence-specific primers were custom-designed to flank nine SNPs within the genetic regions of aforementioned drug metabolizing enzymes. PCR amplification was performed followed by amplicon denaturation by precise temperature ramping in order to distinguish genotypes by melting temperature (Tm). A standardized software algorithm was used to assign amplicons as 'reference' or 'variant' as compared to duplicate reference sequence DNA controls for each SNP. Intra-assay (n=5) precision of Tms for all SNPs was ≤0.19%, while inter-assay (n=20) precision ranged from 0.04% to 0.21%. When compared to a reference method of Sanger sequencing, the HRM assay produced no false negative results, and overcall frequency ranged from 0% to 26%, depending on the SNP. Furthermore, HRM genotyping displayed accuracy over input DNA concentrations ranging from 10 to 200 ng/μL. The presented assay provides a rapid method for the screening for genetic variants in targeted CYP450 regions with a result of 'reference' or 'variant' available within 2 h from receipt of extracted DNA. The method can serve as a screening approach to rapidly identify individuals with variant sequences who should be further investigated by reflexed confirmatory testing for aberrant cytochrome P450 enzymatic activity. Rapid knowledge of variant status may aid in the avoidance of adverse clinical events by allowing for dosing of normal metabolizer patients immediately while identifying the need to wait for confirmatory testing in those patients who are

  9. HE4 Transcription- and Splice Variants-Specific Expression in Endometrial Cancer and Correlation with Patient Survival

    Directory of Open Access Journals (Sweden)

    Shi-Wen Jiang

    2013-11-01

    Full Text Available We investigated the HE4 variant-specific expression patterns in various normal tissues as well as in normal and malignant endometrial tissues. The relationships between mRNA variants and age, body weight, or survival are analyzed. ICAT-labeled normal and endometrial cancer (EC tissues were analyzed with multidimensional liquid chromatography followed by tandem mass spectrometry. Levels of HE4 mRNA variants were measured by real-time PCR. Mean mRNA levels were compared among 16 normal endometrial samples, 14 grade 1 and 14 grade 3 endometrioid EC, 15 papillary serous EC, and 14 normal human tissue samples. The relationship between levels of HE4 variants and EC patient characteristics was analyzed with the use of Pearson correlation test. We found that, although all five HE4 mRNA variants are detectable in normal tissue samples, their expression is highly tissue-specific, with epididymis, trachea, breast and endometrium containing the highest levels. HE4-V0, -V1, and -V3 are the most abundant variants in both normal and malignant tissues. All variants are significantly increased in both endometrioid and papillary serous EC, with higher levels observed in grade 3 endometrioid EC. In the EC group, HE4-V1, -V3, and -V4 levels inversely correlate with EC patient survival, whereas HE4-V0 levels positively correlate with age. HE4 variants exhibit tissue-specific expression, suggesting that each variant may exert distinct functions in normal and malignant cells. HE4 levels appear to correlate with EC patient survival in a variant-specific manner. When using HE4 as a biomarker for EC management, the effects of age should be considered.

  10. High-resolution melting analysis using unlabeled probe and amplicon scanning simultaneously detects several lactase persistence variants

    DEFF Research Database (Denmark)

    Janukonyté, Jurgita; Vestergaard, Else M; Ladefoged, Søren A

    2010-01-01

    Lactase persistence and thereby tolerance to lactose is a common trait in people of Northern European descent. It is linked to the LCT -13910C>T variant located in intron 13 of the MCM6 gene 13.9 kb upstream of the lactase (LCT) gene. In people of African and Middle Eastern descent, lactase...... persistence can be associated with other variants nearby the -13910C>T variant, limiting the use of the -13910C>T-based SNP analysis, e.g. TaqMan assays for the diagnosis of lactose intolerance. Using high-resolution melting analysis, we identified five samples that were heterozygous for the -13915T>G variant...... the -13910C>T and -13915T>G variants in addition to rarer variants surrounding the -13910 site. This new method may contribute to improve the diagnostic performance of the genetic analysis for lactose intolerance....

  11. Family studies to find rare high risk variants in migraine

    DEFF Research Database (Denmark)

    Hansen, Rikke Dyhr; Christensen, Anne Francke; Olesen, Jes

    2017-01-01

    genetic variants with bigger effect size may be involved in the disease. Since migraine has a tendency to cluster in families, a family approach might be the way to find these variants. This is also indicated by identification of migraine-associated loci in classical linkage-analyses in migraine families....... A single migraine study using a candidate-gene approach was performed in 2010 identifying a rare mutation in the TRESK potassium channel segregating in a large family with migraine with aura, but this finding has later become questioned. The technologies of next-generation sequencing (NGS) now provides...... an affordable tool to investigate the genetic variation in the entire exome or genome. The family-based study design using NGS is described in this paper. We also review family studies using NGS that have been successful in finding rare variants in other common complex diseases in order to argue the promising...

  12. Prioritizing single-nucleotide polymorphisms and variants associated with clinical mastitis

    Directory of Open Access Journals (Sweden)

    Suravajhala P

    2017-06-01

    Full Text Available Prashanth Suravajhala,1 Alfredo Benso2 1Department of Molecular Biology and Genetics, Center for Quantitative Genetics and Genomics, Aarhus University, Aarhus, Denmark; 2Department of Control and Computer Engineering, Politecnico di Torino, Torino, Italy Abstract: Next-generation sequencing technology has provided resources to easily explore and identify candidate single-nucleotide polymorphisms (SNPs and variants. However, there remains a challenge in identifying and inferring the causal SNPs from sequence data. A problem with different methods that predict the effect of mutations is that they produce false positives. In this hypothesis, we provide an overview of methods known for identifying causal variants and discuss the challenges, fallacies, and prospects in discerning candidate SNPs. We then propose a three-point classification strategy, which could be an additional annotation method in identifying causalities. Keywords: clinical mastitis, single-nucleotide polymorphisms, variants, associations, diseases, linkage disequilibrium, GWAS

  13. PCSK9 genetic variants and risk of type 2 diabetes

    DEFF Research Database (Denmark)

    Schmidt, Amand F; Swerdlow, Daniel I; Holmes, Michael V

    2017-01-01

    used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using...... diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. METHODS: In this mendelian randomisation study, we...... a standardised analysis plan, meta-analyses, and weighted gene-centric scores. FINDINGS: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL...

  14. Comparison and optimization of in silico algorithms for predicting the pathogenicity of sodium channel variants in epilepsy.

    Science.gov (United States)

    Holland, Katherine D; Bouley, Thomas M; Horn, Paul S

    2017-07-01

    Variants in neuronal voltage-gated sodium channel α-subunits genes SCN1A, SCN2A, and SCN8A are common in early onset epileptic encephalopathies and other autosomal dominant childhood epilepsy syndromes. However, in clinical practice, missense variants are often classified as variants of uncertain significance when missense variants are identified but heritability cannot be determined. Genetic testing reports often include results of computational tests to estimate pathogenicity and the frequency of that variant in population-based databases. The objective of this work was to enhance clinicians' understanding of results by (1) determining how effectively computational algorithms predict epileptogenicity of sodium channel (SCN) missense variants; (2) optimizing their predictive capabilities; and (3) determining if epilepsy-associated SCN variants are present in population-based databases. This will help clinicians better understand the results of indeterminate SCN test results in people with epilepsy. Pathogenic, likely pathogenic, and benign variants in SCNs were identified using databases of sodium channel variants. Benign variants were also identified from population-based databases. Eight algorithms commonly used to predict pathogenicity were compared. In addition, logistic regression was used to determine if a combination of algorithms could better predict pathogenicity. Based on American College of Medical Genetic Criteria, 440 variants were classified as pathogenic or likely pathogenic and 84 were classified as benign or likely benign. Twenty-eight variants previously associated with epilepsy were present in population-based gene databases. The output provided by most computational algorithms had a high sensitivity but low specificity with an accuracy of 0.52-0.77. Accuracy could be improved by adjusting the threshold for pathogenicity. Using this adjustment, the Mendelian Clinically Applicable Pathogenicity (M-CAP) algorithm had an accuracy of 0.90 and a

  15. Human genomic disease variants: a neutral evolutionary explanation.

    Science.gov (United States)

    Dudley, Joel T; Kim, Yuseob; Liu, Li; Markov, Glenn J; Gerold, Kristyn; Chen, Rong; Butte, Atul J; Kumar, Sudhir

    2012-08-01

    Many perspectives on the role of evolution in human health include nonempirical assumptions concerning the adaptive evolutionary origins of human diseases. Evolutionary analyses of the increasing wealth of clinical and population genomic data have begun to challenge these presumptions. In order to systematically evaluate such claims, the time has come to build a common framework for an empirical and intellectual unification of evolution and modern medicine. We review the emerging evidence and provide a supporting conceptual framework that establishes the classical neutral theory of molecular evolution (NTME) as the basis for evaluating disease- associated genomic variations in health and medicine. For over a decade, the NTME has already explained the origins and distribution of variants implicated in diseases and has illuminated the power of evolutionary thinking in genomic medicine. We suggest that a majority of disease variants in modern populations will have neutral evolutionary origins (previously neutral), with a relatively smaller fraction exhibiting adaptive evolutionary origins (previously adaptive). This pattern is expected to hold true for common as well as rare disease variants. Ultimately, a neutral evolutionary perspective will provide medicine with an informative and actionable framework that enables objective clinical assessment beyond convenient tendencies to invoke past adaptive events in human history as a root cause of human disease.

  16. Using Extreme Phenotype Sampling to Identify the Rare Causal Variants of Quantitative Traits in Association Studies

    OpenAIRE

    Li, Dalin; Lewinger, Juan Pablo; Gauderman, William J.; Murcray, Cassandra Elizabeth; Conti, David

    2011-01-01

    Variants identified in recent genome-wide association studies based on the common-disease common-variant hypothesis are far from fully explaining the hereditability of complex traits. Rare variants may, in part, explain some of the missing hereditability. Here, we explored the advantage of the extreme phenotype sampling in rare-variant analysis and refined this design framework for future large-scale association studies on quantitative traits. We first proposed a power calculation approach fo...

  17. High prevalence of genetic variants previously associated with Brugada syndrome in new exome data

    DEFF Research Database (Denmark)

    Risgaard, B; Jabbari, R; Refsgaard, L

    2013-01-01

    More than 300 variants in 12 genes have been associated with Brugada syndrome (BrS) which has a prevalence ranging between 1:2000 and 1:100,000. Until recently, there has been little knowledge regarding the distribution of genetic variations in the general population. This problem was partly solved......, when exome data from the NHLI GO Exome Sequencing Project (ESP) was published. In this study, we aimed to report the prevalence of previously BrS-associated variants in the ESP population. We performed a search in ESP for variants previously associated with BrS. In addition, four variants in ESP were...... to a surprisingly high genotype prevalence of 1:23 (274:6258). Genotyping the four common ESP-derived variants CACNA2D1 S709N, SCN5A F2004L, CACNB2 S143F, and CACNB2 T450I in the Danish controls, we found a genotype prevalence comparable with that found in ESP. We suggest that exome data are used in research...

  18. Evidence of trem2 variant associated with triple risk of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Zainularifeen Abduljaleel

    Full Text Available Alzheimer's disease is one of the main causes of dementia among elderly individuals and leads to the neurodegeneration of different areas of the brain, resulting in memory impairments and loss of cognitive functions. Recently, a rare variant that is associated with 3-fold higher risk of Alzheimer's disease onset has been found. The rare variant discovered is a missense mutation in the loop region of exon 2 of Trem2 (rs75932628-T, Arg47His. The aim of this study was to investigate the evidence for potential structural and functional significance of Trem2 gene variant (Arg47His through molecular dynamics simulations. Our results showed the alteration caused due to the variant in TREM2 protein has significant effect on the ligand binding affinity as well as structural configuration. Based on molecular dynamics (MD simulation under salvation, the results confirmed that native form of the variant (Arg47His might be responsible for improved compactness, hence thereby improved protein folding. Protein simulation was carried out at different temperatures. At 300K, the deviation of the theoretical model of TREM2 protein increased from 2.0 Å at 10 ns. In contrast, the deviation of the Arg47His mutation was maintained at 1.2 Å until the end of the simulation (t = 10 ns, which indicated that Arg47His had reached its folded state. The mutant residue was a highly conserved region and was similar to "immunoglobulin V-set" and "immunoglobulin-like folds". Taken together, the result from this study provides a biophysical insight on how the studied variant could contribute to the genetic susceptibility to Alzheimer's disease.

  19. U1 small nuclear RNA variants differentially form ribonucleoprotein particles in vitro.

    Science.gov (United States)

    Somarelli, Jason A; Mesa, Annia; Rodriguez, Carol E; Sharma, Shalini; Herrera, Rene J

    2014-04-25

    The U1 small nuclear (sn)RNA participates in splicing of pre-mRNAs by recognizing and binding to 5' splice sites at exon/intron boundaries. U1 snRNAs associate with 5' splice sites in the form of ribonucleoprotein particles (snRNPs) that are comprised of the U1 snRNA and 10 core components, including U1A, U1-70K, U1C and the 'Smith antigen', or Sm, heptamer. The U1 snRNA is highly conserved across a wide range of taxa; however, a number of reports have identified the presence of expressed U1-like snRNAs in multiple species, including humans. While numerous U1-like molecules have been shown to be expressed, it is unclear whether these variant snRNAs have the capacity to form snRNPs and participate in splicing. The purpose of the present study was to further characterize biochemically the ability of previously identified human U1-like variants to form snRNPs and bind to U1 snRNP proteins. A bioinformatics analysis provided support for the existence of multiple expressed variants. In vitro gel shift assays, competition assays, and immunoprecipitations (IPs) revealed that the variants formed high molecular weight assemblies to varying degrees and associated with core U1 snRNP proteins to a lesser extent than the canonical U1 snRNA. Together, these data suggest that the human U1 snRNA variants analyzed here are unable to efficiently bind U1 snRNP proteins. The current work provides additional biochemical insights into the ability of the variants to assemble into snRNPs. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. A Nested Case-Control Study of Luteinizing Hormone Variants and Risk of Breast Cancer

    Science.gov (United States)

    1999-10-01

    study has addressed the relationship of the presence of the variant LH to clinical and hormonal parameters among women with polycystic ovaries as...compared to healthy subjects (6). In this study, the variant was appreciably more frequent in obese women with polycystic ovaries than in normal women...immunological LH- 13-subunit variant in a UK population of healthy women and women with polycystic ovary syndrome. Clin Endocrinol. 1995; 43:297-303

  1. Análisis de variantes de HPV-16 como marcador molecular antropólogico

    Directory of Open Access Journals (Sweden)

    Badano, Ines

    2007-01-01

    Full Text Available El Virus Papiloma Humano tipo 16 (HPV16 es el principal responsable del desarrollo del cáncer de cuello uterino. Además de su significado clínico, el estudio de la variación genética en las regiones E6, L1 y LCR de este virus ha permitido identificar variantes específicas de diferentes áreas geográficas. Este descubrimiento sugiere una antigua propagación del HPV16 y su coevolución con el género humano. En este contexto, las variantes podrían servir como marcador molecular antropológico, aportando nuevos datos al análisis de patrones migratorios humanos. El objetivo del trabajo fue determinar las variantes de HPV16 en las regiones genéticas E6 y L1 que infectan mujeres guaraníes de Misiones. Para ello se analizaron 39 muestras de cepillados cervicales de mujeres guaraníes infectadas con HPV16. Las variantes en E6 y L1 se identificaron por PCR e hibridación en dot blot. Los resultados obtenidos fueron: el 77% de las variantes Europeas, 20% Africanas y 3% Asiático Americanas. La baja prevalencia de variantes Asiático Americanas coincide con lo reportado por Picconi y col, 2002 para mujeres quechuas, y haría suponer una limitada diseminación del HPV16 durante la época prehispánica. El predominio de las variantes Europeas podría ser resultado de la colonización española y la inmigración europea, mientras que el tráfico de esclavos negros explicaría la presencia de variantes Africanas. Por otra parte, la hipótesis de competencia viral tampoco puede ser descartada.

  2. 201Tl uptake in variant angina: probable demonstration of myocardial reactive hyperemia in man

    International Nuclear Information System (INIS)

    Kronenberg, M.W.; Robertson, R.M.; Born, M.L.; Steckley, R.A.; Robertson, D.; Friesinger, G.C.

    1982-01-01

    Myocardial thallium scintigraphy was performed in four subjects with variant angina and in one subject with isolated, fixed coronary obstruction. Three subjects with variant angina had short episodes of ischemic ST-segment elevation that lasted 20--100 seconds. Thallium scintigrams demonstrated excess uptake in regions judged to be ischemic by angiographic and electrocardiographic criteria. Two subjects, one with variant angina and the other with a fixed coronary lesion, had prolonged episodes of ischemia that lasted 390--900 seconds. Both had reduced thallium uptake in the ischemic regions. We conclude that myocardial reactive hyperemia is the cause of excess thallium uptake in patients with variant angina who have short episodes of myocardial ischemia

  3. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

    Science.gov (United States)

    Johnston, Jennifer J; van der Smagt, Jasper J; Rosenfeld, Jill A; Pagnamenta, Alistair T; Alswaid, Abdulrahman; Baker, Eva H; Blair, Edward; Borck, Guntram; Brinkmann, Julia; Craigen, William; Dung, Vu Chi; Emrick, Lisa; Everman, David B; van Gassen, Koen L; Gulsuner, Suleyman; Harr, Margaret H; Jain, Mahim; Kuechler, Alma; Leppig, Kathleen A; McDonald-McGinn, Donna M; Can, Ngoc Thi Bich; Peleg, Amir; Roeder, Elizabeth R; Rogers, R Curtis; Sagi-Dain, Lena; Sapp, Julie C; Schäffer, Alejandro A; Schanze, Denny; Stewart, Helen; Taylor, Jenny C; Verbeek, Nienke E; Walkiewicz, Magdalena A; Zackai, Elaine H; Zweier, Christiane; Zenker, Martin; Lee, Brendan; Biesecker, Leslie G

    2018-02-22

    PurposeTo characterize the molecular genetics of autosomal recessive Noonan syndrome.MethodsFamilies underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction.ResultsTwelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings.ConclusionThese clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.Genet Med advance online publication, 22 February 2018; doi:10.1038/gim.2017.249.

  4. A clinically driven variant prioritization framework outperforms purely computational approaches for the diagnostic analysis of singleton WES data.

    Science.gov (United States)

    Stark, Zornitza; Dashnow, Harriet; Lunke, Sebastian; Tan, Tiong Y; Yeung, Alison; Sadedin, Simon; Thorne, Natalie; Macciocca, Ivan; Gaff, Clara; Oshlack, Alicia; White, Susan M; James, Paul A

    2017-11-01

    Rapid identification of clinically significant variants is key to the successful application of next generation sequencing technologies in clinical practice. The Melbourne Genomics Health Alliance (MGHA) variant prioritization framework employs a gene prioritization index based on clinician-generated a priori gene lists, and a variant prioritization index (VPI) based on rarity, conservation and protein effect. We used data from 80 patients who underwent singleton whole exome sequencing (WES) to test the ability of the framework to rank causative variants highly, and compared it against the performance of other gene and variant prioritization tools. Causative variants were identified in 59 of the patients. Using the MGHA prioritization framework the average rank of the causative variant was 2.24, with 76% ranked as the top priority variant, and 90% ranked within the top five. Using clinician-generated gene lists resulted in ranking causative variants an average of 8.2 positions higher than prioritization based on variant properties alone. This clinically driven prioritization approach significantly outperformed purely computational tools, placing a greater proportion of causative variants top or in the top 5 (permutation P-value=0.001). Clinicians included 40 of the 49 WES diagnoses in their a priori list of differential diagnoses (81%). The lists generated by PhenoTips and Phenomizer contained 14 (29%) and 18 (37%) of these diagnoses respectively. These results highlight the benefits of clinically led variant prioritization in increasing the efficiency of singleton WES data analysis and have important implications for developing models for the funding and delivery of genomic services.

  5. Importance of non-synonymous OCA2 variants in human eye colour prediction

    DEFF Research Database (Denmark)

    Andersen, Jeppe Dyrberg; Pietroni, Carlotta; Johansen, Peter

    2016-01-01

    in the promotor region of OCA2 (OMIM #611409). Nevertheless, many eye colors cannot be explained by only considering rs12913832:A>G. Methods: In this study, we searched for additional variants in OCA2 to explain human eye color by sequencing a 500 kbp region, encompassing OCA2 and its promotor region. Results: We...... identified three nonsynonymous OCA2 variants as important for eye color, including rs1800407:G>A (p.Arg419Gln) and two variants, rs74653330:A>T (p.Ala481Thr) and rs121918166:G>A (p.Val443Ile), not previously described as important for eye color variation. It was shown that estimated haplotypes consisting...

  6. Diffuse sclerosing variant of papillary thyroid carcinoma: case report

    International Nuclear Information System (INIS)

    Lee, Seung Chan; Kim, Dong Wook

    2006-01-01

    Diffuse sclerosing papillary carcinoma (DSPC) is a variant of papillary thyroid carcinoma (PTC), but it shows more aggressive clinical course and a poorer prognosis than the other types of PTC. Most PTCs show a focal nodular pattern in the thyroid on the imaging modalities, but DSPC reveals a diffuse infiltrating configuration in the thyroid without any focal nodular lesion. To our knowledge, there are scant radiological reports of diffuse sclerosing variant of papillary thyroid carcinoma. In this report, we present the case of a patient with DSPC who showed the characteristic findings on sonography and computed tomography

  7. Perforating pilomatrixoma showing atypical presentation: A rare clinical variant

    Directory of Open Access Journals (Sweden)

    Nevra Seyhan

    2018-03-01

    Full Text Available Pilomatrixoma, also known as calcifying epithelioma of Malherbe, is a rare benign skin tumor arising from hair follicle stem cells. The most common localization is the head and neck region. Female/male ratio is 3/2. It shows deep subcutaneous placement and occurs in the first two decades of life. Its diameter ranges from 0.5 cm to 3 cm. Multiple lesions are rarely seen. Histopathologically it is characterized by basoloid and ghost cells. Perforating type is a rare clinical variant. Treatment is surgical excision. Our case is presented to draw attention to a rare clinical variant of pilomatrixioma.

  8. Discovery and functional annotation of SIX6 variants in primary open-angle glaucoma.

    Directory of Open Access Journals (Sweden)

    Megan Ulmer Carnes

    Full Text Available Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR = 1.32, p = 3.87×10(-11. SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345, which was associated significantly with POAG (OR = 1.27, p = 4.2×10(-10 in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141 have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141. Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss.

  9. Characterization and functional analysis of four HYH splicing variants in Arabidopsis hypocotyl elongation.

    Science.gov (United States)

    Li, Chen; Zheng, Lanlan; Zhang, Jingxuan; Lv, Yanxia; Liu, Jianping; Wang, Xuanbin; Palfalvi, Gergo; Wang, Guodong; Zhang, Yonghong

    2017-07-01

    Arabidopsis thaliana LONG HYPOCOTYL5 (HY5) is a positive regulator of the light signaling pathway. The hy5 mutant has an elongated hypocotyl in all light conditions, whereas the hy5 homolog (hyh) mutant has a very weak phenotype, but only in blue light. However, overexpression of HYH rescues the elongated hypocotyl phenotype in the hy5 null mutant. Here, we report the identification of four HYH splicing variants in Arabidopsis. Alternative splicing in the 5' region of the HYH gene occurred such that the proteins encoded by all four HYH variants retained their bZIP domain. In hypocotyl tissue, transcript levels of HYH.2, HYH.3, and HYH.4 were higher than those of HYH.1. Like HY5, all HYH variants were induced by light. Functional analysis of the four HYH variants, based on their abilities to complement the hy5 mutant, indicated that they have similar roles in hypocotyl development, and may function redundantly with HY5. Our results indicate that the bZIP domain in HYH is critical for the function of four variants in the compensation of hy5 mutant in hypocotyl development. Additionally, while HY5/HYH is found in plant species ranging from green algae to flowering plants, the potential alternative splicing events are distinct in different species, with certain HYH variants found with greater frequency in some species than others. Copyright © 2017. Published by Elsevier B.V.

  10. ISVASE: identification of sequence variant associated with splicing event using RNA-seq data.

    Science.gov (United States)

    Aljohi, Hasan Awad; Liu, Wanfei; Lin, Qiang; Yu, Jun; Hu, Songnian

    2017-06-28

    Exon recognition and splicing precisely and efficiently by spliceosome is the key to generate mature mRNAs. About one third or a half of disease-related mutations affect RNA splicing. Software PVAAS has been developed to identify variants associated with aberrant splicing by directly using RNA-seq data. However, it bases on the assumption that annotated splicing site is normal splicing, which is not true in fact. We develop the ISVASE, a tool for specifically identifying sequence variants associated with splicing events (SVASE) by using RNA-seq data. Comparing with PVAAS, our tool has several advantages, such as multi-pass stringent rule-dependent filters and statistical filters, only using split-reads, independent sequence variant identification in each part of splicing (junction), sequence variant detection for both of known and novel splicing event, additional exon-exon junction shift event detection if known splicing events provided, splicing signal evaluation, known DNA mutation and/or RNA editing data supported, higher precision and consistency, and short running time. Using a realistic RNA-seq dataset, we performed a case study to illustrate the functionality and effectiveness of our method. Moreover, the output of SVASEs can be used for downstream analysis such as splicing regulatory element study and sequence variant functional analysis. ISVASE is useful for researchers interested in sequence variants (DNA mutation and/or RNA editing) associated with splicing events. The package is freely available at https://sourceforge.net/projects/isvase/ .

  11. Venous variants and anomalies on routine abdominal multi-detector row CT

    International Nuclear Information System (INIS)

    Koc, Zafer; Ulusan, Serife; Oguzkurt, Levent; Tokmak, Naime

    2007-01-01

    Objective: This study aims to determine the types and prevalence rates of anatomic variations of the hepatic veins, portal vein, inferior vena cava and renal veins, and to establish statistical correlations between various anomalies and frequency differences between male and female using multi-detector row computed tomography (CT). Materials and methods: One thousand one hundred and twenty patients (588 men, 532 women) were evaluated with routine abdominal CT. Frequencies of different variants were noted and compared, and correlations between three categories of variation were tested. Results: In total, 1261 abdominal vein variants and anomalies were identified in 756 (67.5%) of 1120 patients. Six hundred and forty-two hepatic vein variants were detected in 468 (41.8%) patients. One or more inferior right hepatic veins were identified in 356 (31.8%) individuals, and tributary hepatic veins were detected in 147 (13.1%) patients. Portal vein variations and anomalies were observed in 307 (27.4%) cases. The most frequent of these was trifurcation (139 patients, 12.4%). A total of 311 inferior vena cava and renal vein variants were identified in 258 (23%) cases. Six patients (0.5%) exhibited inferior vena cava anomalies, 62 (5.5%) had circumaortic renal veins, 53 (4.7%) had retroaortic renal veins, and 210 (18.8%) had multiple renal veins. Conclusion: The prevalence of abdominal vein variations is high, and routine abdominal CT demonstrates these abnormalities very well. The data suggest that hepatic vein variants and multiple right renal veins are more frequent in women than in men, and that hepatic vein variation is correlated with portal vein variation

  12. Venous variants and anomalies on routine abdominal multi-detector row CT

    Energy Technology Data Exchange (ETDEWEB)

    Koc, Zafer [Baskent University, School of Medicine, Department of Radiology, Adana (Turkey)]. E-mail: koczafer@gmail.com; Ulusan, Serife [Baskent University, School of Medicine, Department of Radiology, Adana (Turkey); Oguzkurt, Levent [Baskent University, School of Medicine, Department of Radiology, Adana (Turkey); Tokmak, Naime [Baskent University, School of Medicine, Department of Radiology, Adana (Turkey)

    2007-02-15

    Objective: This study aims to determine the types and prevalence rates of anatomic variations of the hepatic veins, portal vein, inferior vena cava and renal veins, and to establish statistical correlations between various anomalies and frequency differences between male and female using multi-detector row computed tomography (CT). Materials and methods: One thousand one hundred and twenty patients (588 men, 532 women) were evaluated with routine abdominal CT. Frequencies of different variants were noted and compared, and correlations between three categories of variation were tested. Results: In total, 1261 abdominal vein variants and anomalies were identified in 756 (67.5%) of 1120 patients. Six hundred and forty-two hepatic vein variants were detected in 468 (41.8%) patients. One or more inferior right hepatic veins were identified in 356 (31.8%) individuals, and tributary hepatic veins were detected in 147 (13.1%) patients. Portal vein variations and anomalies were observed in 307 (27.4%) cases. The most frequent of these was trifurcation (139 patients, 12.4%). A total of 311 inferior vena cava and renal vein variants were identified in 258 (23%) cases. Six patients (0.5%) exhibited inferior vena cava anomalies, 62 (5.5%) had circumaortic renal veins, 53 (4.7%) had retroaortic renal veins, and 210 (18.8%) had multiple renal veins. Conclusion: The prevalence of abdominal vein variations is high, and routine abdominal CT demonstrates these abnormalities very well. The data suggest that hepatic vein variants and multiple right renal veins are more frequent in women than in men, and that hepatic vein variation is correlated with portal vein variation.

  13. Lipid Cell and Micropapillary Variants of Urothelial Carcinoma of the Ureter

    Directory of Open Access Journals (Sweden)

    Yu Miyama

    2015-11-01

    Full Text Available We report on a case of urothelial carcinoma (UC with lipid cell and micropapillary variants in the ureter. A 64-year-old man presented with gross hematuria. Urinary cytology revealed the presence of atypical urothelial cells. Computed tomography and drip infusion/retrograde pyelography identified a mass-occupying lesion in the left mid-ureter, as well as left hydronephrosis. A clinical diagnosis of left ureteral cancer was given and the patient underwent left nephroureterectomy. Microscopically, the major component of the tumor was a conventional high-grade UC. In the invasive region, however, lipid cell and micropapillary variants of UC were also observed. Upon immunohistochemical analysis, all of the components were diffusely positive for cytokeratin 7 and p53. Intense membranous expression of human epidermal growth factor receptor 2 (HER2 was also observed in both the lipid cell and micropapillary variants of UC, whereas weak and incomplete staining was observed in most regions of the conventional UC. The pathological stage was pT3 N2. Multiple times, the patient experienced recurrence of the UC in the urinary bladder and urethra. Although the patient underwent total cystectomy and urethrectomy, 52 months following the initial surgery, signs of local recurrence developed, as well as multiple lymph node and bone metastases. The patient died 75 months following the initial surgery. To the best of our knowledge, this is the first reported case of a lipid cell variant of ureteral UC. The overexpression of HER2 may be associated with both the lipid cell and micropapillary variants of UC.

  14. Rapid preparative separation of monoclonal antibody charge variants using laterally-fed membrane chromatography.

    Science.gov (United States)

    Sadavarte, Rahul; Madadkar, Pedram; Filipe, Carlos Dm; Ghosh, Raja

    2018-01-15

    Monoclonal antibodies undergo various forms of chemical transformation which have been shown to cause loss in efficacy and alteration in pharmacokinetic properties of these molecules. Such modified antibody molecules are known as variants. They also display physical properties such as charge that are different from intact antibody molecules. However, the difference in charge is very subtle and separation based on it is quite challenging. Charge variants are usually separated using ion-exchange column chromatography or isoelectric focusing. In this paper, we report a rapid and scalable method for fractionating monoclonal antibody charge variants, based on the use of cation exchange laterally-fed membrane chromatography (LFMC). Starting with a sample of monoclonal antibody hIgG1-CD4, three well-resolved fractions were obtained using either pH or salt gradient. These fractions were identified as acidic, neutral and basic variants. Each of these fractions contained intact heavy and light chains and so antibody fragmentation had no role in variant generation. The separation was comparable to that using column chromatography but was an order of magnitude faster. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Association between genetic variants of the clock gene and obesity and sleep duration.

    Science.gov (United States)

    Valladares, Macarena; Obregón, Ana María; Chaput, Jean-Philippe

    2015-12-01

    Obesity is a multifactorial disease caused by the interaction of genetic and environmental factors related to lifestyle aspects. It has been shown that reduced sleep is associated with increased body mass index (BMI). Circadian Locomotor Output Cycles Kaput (CLOCK) gene variants have also been associated with obesity. The objective of this mini-review was to discuss the available literature related to CLOCK gene variants associated with adiposity and sleep duration in humans. In total, 16 articles complied with the terms of the search that reported CLOCK variants associated with sleep duration, energy intake, and BMI. Overall, six CLOCK single nucleotide polymorphisms (SNPs) have been associated with sleep duration, and three variants have been associated with energy intake variables. Overall, the most studied area has been the association of CLOCK gene with obesity; close to eight common variants have been associated with obesity. The most studied CLOCK SNP in different populations is rs1801260, and most of these populations correspond to European populations. Collectively, identifying at risk CLOCK genotypes is a new area of research that may help identify individuals who are more susceptible to overeating and gaining weight when exposed to short sleep durations.

  16. Identification of Alternative Splice Variants Using Unique Tryptic Peptide Sequences for Database Searches.

    Science.gov (United States)

    Tran, Trung T; Bollineni, Ravi C; Strozynski, Margarita; Koehler, Christian J; Thiede, Bernd

    2017-07-07

    Alternative splicing is a mechanism in eukaryotes by which different forms of mRNAs are generated from the same gene. Identification of alternative splice variants requires the identification of peptides specific for alternative splice forms. For this purpose, we generated a human database that contains only unique tryptic peptides specific for alternative splice forms from Swiss-Prot entries. Using this database allows an easy access to splice variant-specific peptide sequences that match to MS data. Furthermore, we combined this database without alternative splice variant-1-specific peptides with human Swiss-Prot. This combined database can be used as a general database for searching of LC-MS data. LC-MS data derived from in-solution digests of two different cell lines (LNCaP, HeLa) and phosphoproteomics studies were analyzed using these two databases. Several nonalternative splice variant-1-specific peptides were found in both cell lines, and some of them seemed to be cell-line-specific. Control and apoptotic phosphoproteomes from Jurkat T cells revealed several nonalternative splice variant-1-specific peptides, and some of them showed clear quantitative differences between the two states.

  17. Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

    DEFF Research Database (Denmark)

    Mahajan, Anubha

    2018-01-01

    , compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex...

  18. Evaluation of exome variants using the Ion Proton Platform to sequence error-prone regions.

    Science.gov (United States)

    Seo, Heewon; Park, Yoomi; Min, Byung Joo; Seo, Myung Eui; Kim, Ju Han

    2017-01-01

    The Ion Proton sequencer from Thermo Fisher accurately determines sequence variants from target regions with a rapid turnaround time at a low cost. However, misleading variant-calling errors can occur. We performed a systematic evaluation and manual curation of read-level alignments for the 675 ultrarare variants reported by the Ion Proton sequencer from 27 whole-exome sequencing data but that are not present in either the 1000 Genomes Project and the Exome Aggregation Consortium. We classified positive variant calls into 393 highly likely false positives, 126 likely false positives, and 156 likely true positives, which comprised 58.2%, 18.7%, and 23.1% of the variants, respectively. We identified four distinct error patterns of variant calling that may be bioinformatically corrected when using different strategies: simplicity region, SNV cluster, peripheral sequence read, and base inversion. Local de novo assembly successfully corrected 201 (38.7%) of the 519 highly likely or likely false positives. We also demonstrate that the two sequencing kits from Thermo Fisher (the Ion PI Sequencing 200 kit V3 and the Ion PI Hi-Q kit) exhibit different error profiles across different error types. A refined calling algorithm with better polymerase may improve the performance of the Ion Proton sequencing platform.

  19. Evaluation of exome variants using the Ion Proton Platform to sequence error-prone regions.

    Directory of Open Access Journals (Sweden)

    Heewon Seo

    Full Text Available The Ion Proton sequencer from Thermo Fisher accurately determines sequence variants from target regions with a rapid turnaround time at a low cost. However, misleading variant-calling errors can occur. We performed a systematic evaluation and manual curation of read-level alignments for the 675 ultrarare variants reported by the Ion Proton sequencer from 27 whole-exome sequencing data but that are not present in either the 1000 Genomes Project and the Exome Aggregation Consortium. We classified positive variant calls into 393 highly likely false positives, 126 likely false positives, and 156 likely true positives, which comprised 58.2%, 18.7%, and 23.1% of the variants, respectively. We identified four distinct error patterns of variant calling that may be bioinformatically corrected when using different strategies: simplicity region, SNV cluster, peripheral sequence read, and base inversion. Local de novo assembly successfully corrected 201 (38.7% of the 519 highly likely or likely false positives. We also demonstrate that the two sequencing kits from Thermo Fisher (the Ion PI Sequencing 200 kit V3 and the Ion PI Hi-Q kit exhibit different error profiles across different error types. A refined calling algorithm with better polymerase may improve the performance of the Ion Proton sequencing platform.

  20. Biochemical characterization and structural modeling of human cathepsin E variant 2 in comparison to the wild-type protein

    Science.gov (United States)

    Puizdar, Vida; Zajc, Tajana; Žerovnik, Eva; Renko, Miha; Pieper, Ursula; Eswar, Narayanan; Šali, Andrej; Dolenc, Iztok; Turk, Vito

    2014-01-01

    Cathepsin E splice variant 2 appears in a number of gastric carcinoma. Here, we report detecting this variant in HeLa cells using polyclonal antibodies and biotinylated inhibitor pepstatin A. An overexpression of GFP fusion proteins of cathepsin E and its splice variant within HEK-293T cells was performed to show their localization. Their distribution under a fluorescence microscope showed that they are colocalized. We also expressed variant 1 and variant 2 of cathepsins E, with propeptide and without it, in Echerichia coli. After refolding from the inclusion bodies, the enzymatic activity and circular dichroism spectra of the splice variant 2 were compared to those of the wild-type mature active cathepsins E. While full-length cathepsin E variant1 is activated at acid pH, the splice variant remains inactive. In contrast to the active cathepsin E, the splice variant 2 predominantly assumes β-sheet structure, prone to oligomerization, at least under in vitro conditions, as shown by Atomic Force Microscopy as shallow disk-like particles. A comparative structure model of splice variant 2 was computed based on its alignment to the known structure of cathepsin E intermediate (Protein Data Bank code 1TZS), and used to rationalize its conformational properties and loss of activity. PMID:22718633

  1. Report of a rare anatomic variant

    DEFF Research Database (Denmark)

    De Brucker, Y; Ilsen, B; Muylaert, C

    2015-01-01

    We report the CT findings in a case of partial anomalous pulmonary venous return (PAPVR) from the left upper lobe in an adult. PAPVR is an anatomic variant in which one to three pulmonary veins drain into the right atrium or its tributaries, rather than into the left atrium. This results in a left...

  2. CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity.

    Science.gov (United States)

    Sata, F; Sapone, A; Elizondo, G; Stocker, P; Miller, V P; Zheng, W; Raunio, H; Crespi, C L; Gonzalez, F J

    2000-01-01

    To determine the existence of mutant and variant CgammaP3A4 alleles in three racial groups and to assess functions of the variant alleles by complementary deoxyribonucleic acid (cDNA) expression. A bacterial artificial chromosome that contains the complete CgammaP3A4 gene was isolated and the exons and surrounding introns were directly sequenced to develop primers to polymerase chain reaction (PCR) amplify and sequence the gene from lymphocyte DNA. DNA samples from Chinese, black, and white subjects were screened. Mutating the affected amino acid in the wild-type cDNA and expressing the variant enzyme with use of the baculovirus system was used to functionally evaluate the variant allele having a missense mutation. To investigate the existence of mutant and variant CgammaP3A4 alleles in humans, all 13 exons and the 5'-flanking region of the human CgammaP3A4 gene in three racial groups were sequenced and four alleles were identified. An A-->G point mutation in the 5'-flanking region of the human CgammaP3A4 gene, designated CgammaP3A4*1B, was found in the three different racial groups. The frequency of this allele in a white population was 4.2%, whereas it was 66.7% in black subjects. The CgammaP3A4*1B allele was not found in Chinese subjects. A second variant allele, designated CgammaP3A4*2, having a Ser222Pro change, was found at a frequency of 2.7% in the white population and was absent in the black subjects and Chinese subjects analyzed. Baculovirus-directed cDNA expression revealed that the CYP3A4*2 P450 had a lower intrinsic clearance for the CYP3A4 substrate nifedipine compared with the wild-type enzyme but was not significantly different from the wild-type enzyme for testosterone 6beta-hydroxylation. Another rare allele, designated CgammaP3A4*3, was found in a single Chinese subject who had a Met445Thr change in the conserved heme-binding region of the P450. These are the first examples of potential function polymorphisms resulting from missense mutations in

  3. Hemoglobin analyses in the Netherlands reveal more than 80 different variants including six novel ones.

    Science.gov (United States)

    van Zwieten, Rob; Veldthuis, Martijn; Delzenne, Barend; Berghuis, Jeffrey; Groen, Joke; Ait Ichou, Fatima; Clifford, Els; Harteveld, Cornelis L; Stroobants, An K